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Flashcards in Drugs Deck (29):
1

Levodopa

• Most effective drug for treatment of symptoms
– Esp ____________
– Less effective for ____________

Levodopa

• Most effective drug for treatment of symptoms
– Esp bradykinesia & rigidity
– Less effective for speech, postural reflex & gait disturbances

2


• Dopamine cannot cross the blood-brain-barrier

• Peripheral conversion of levodopa to dopamine
– Catalysed by ___________
– Dopamine at peripheral causes__________

• Dopamine cannot cross the blood-brain-barrier
• Peripheral conversion of levodopa to dopamine
– Catalysed by DOPA decarboxylase, MAO, COMT
– Dopamine at peripheral causes Nausea / vomitting, hypotension

3

Levodopa
• Pharmacokinetics

– Absorbed in proximal part of small intestine
– Bioavailability:
• Levodopa : ~_____
• With benserazide or carbidopa : ~_____

–Absorbed by an active saturable carrier system for large neutral amino acids e.g. tryptophan

– Absorption ___________ with high fat or high protein meals.
– Note that levodopa itself modifies gastric emptying -> may lead to erratic absorption

Levodopa
• Pharmacokinetics

– Absorbed in proximal part of small intestine
– Bioavailability:
• Levodopa : ~33%
• With benserazide or carbidopa : ~75%

–Absorbed by an active saturable carrier system for large neutral amino acids e.g. tryptophan

– Absorption ↓ with high fat or high protein meals.
– Note that levodopa itself modifies gastric emptying -> may lead to erratic absorption

4

Levodopa

• DOPA decarboylase inhibitors (DCI)
• Do not cross the BBB
• 75mg-100mg daily required to saturate dopa decarboxylase

• DCI : Levodopa
– 1:4 (Sinemet, Madopar) --> 25:100
– 1:10 (Sinemet)

Sinemet = levodopa + Carbidopa
Madopar = levodopa + benserazide

Levodopa

• DOPA decarboylase inhibitors (DCI)
• Do not cross the BBB
• 75mg-100mg daily required to saturate dopa decarboxylase

• DCI : Levodopa
– 1:4 (Sinemet, Madopar) --> 25:100
– 1:10 (Sinemet)

Sinemet = levodopa + Carbidopa
Madopar = levodopa + benserazide

5

Levodopa

– motor problems
• “on-off” phenomenon
– ON = response to levodopa,
– OFF = no response to levodopa

– Unpredictable, not related to dose/dosing interval
– “throwing a light switch”
– Mechanism unclear
– Difficult to control with meds

• “wearing off” – Effect of levodopa wanes before the end of the dosing interval – Shortened “ON” time – Associated with disease progression

Levodopa

– motor problems
• “on-off” phenomenon
– ON = response to levodopa,
– OFF = no response to levodopa

– Unpredictable, not related to dose/dosing interval
– “throwing a light switch”
– Mechanism unclear
– Difficult to control with meds

• “wearing off” – Effect of levodopa wanes before the end of the dosing interval – Shortened “ON” time – Associated with disease progression

6

Levodopa – sustained release forms

• Designed to release levodopa/DCI over a longer period (about ______________ hrs)
• _____________ bioavailability
– Dose adjustments may be needed when switching between immediate and controlled release forms
– IR to CR : generally ____________ dose needed
– CR to IR : generally ___________ dose needed

• Designed to release levodopa/DCI over a longer period (about 4-6 hrs)
• Lower bioavailability

– Dose adjustments may be needed when switching between immediate and controlled release forms
– IR to CR : generally INCREASE dose needed (15-50%)
– CR to IR : generally DECREASE dose needed

7

Levodopa – sustained release forms INDICATION

• Useful for stiffness on waking
--> DECREASE Stiffness on waking

• Sinemet SR – X crush
• Madopar HBS – X open capsule

8

Dopamine agonists

• Ergot derivatives
– Bromocriptine
– Cabergoline
– Pergolide

• Non-Ergot derivatives
– Ropinirole
– Pramipexole
– Rotigotine (transdermal)
– Apomorphine (subcut)

9

transdermal patch

Rotigotine --> non-ergot derivatives dopamine agonists

10

Dopamine agonists
• Mechanism of action
– Act on dopamine (D2) receptors in the basal ganglia. – Mimic action of dopamine

• Pharmacokinetics
– Ergot derived : _______F than non-ergot derived, _________________________________
– _______half-life & duration of action than levodopa
– __________: mainly metabolised by the liver, to inactive metabolites ____________
– ___________: excreted largely unchanged in the urine
___________

Dopamine agonists
• Mechanism of action
– Act on dopamine (D2) receptors in the basal ganglia. – Mimic action of dopamine

• Pharmacokinetics
– Ergot derived : lower F than non-ergot derived, due to extensive first –pass metabolism
– Longer half-life & duration of action than levodopa
– Ropinirole : mainly metabolised by the liver, to inactive metabolites => Need to adjust dose and monitoring in liver disease
– Pramipexole : excreted largely unchanged in the urine => Need to adjust dose and monitoring in renal disease

11

Dopamine agonists
• < motor complications than levodopa but…
• > hallucinations, sleep disturbances, leg oedema, orthostatic hypotension
• No clinically significant differences in efficacy between agents
• Frequently preferred over levodopa in younger patients

Dopamine agonists
• < motor complications than levodopa but…
• > hallucinations, sleep disturbances, leg oedema, orthostatic hypotension
• No clinically significant differences in efficacy between agents
• Frequently preferred over levodopa in younger patients

12

Dopamine agonists
Place in the management of PD

• Monotherapy in young-onset PD
• Adjunct to levodopa in moderate/severe PD
• Management of motor complications caused by levodopa
• Neuroprotection, disease modification??
– Not proven

Dopamine agonists
Place in the management of PD

• Monotherapy in young-onset PD
• Adjunct to levodopa in moderate/severe PD
• Management of motor complications caused by levodopa
• Neuroprotection, disease modification??
– Not proven

13

Dopamine agonists
Additional points to note
• ______is not registered in S’pore
• __________require refrigeration
• _________is marketed under 2 different brand names
– Dostinex® (0..5mg)
– Cabaser® (1mg, 2mg) –> not available in S’pore
• _______& _______-are available in both immediate-release and sustained-release forms.

Dopamine agonists
Additional points to note
• Pergolide is not registered in S’pore
• Rotigotine patches require refrigeration
• Cabergoline is marketed under 2 different brand names
– Dostinex® (0..5mg)
– Cabaser® (1mg, 2mg) –> not available in S’pore
• Pramipexole & ropinirole are available in both immediate-release and sustained-release forms.

14

Monoamine Oxidase B Inhibitors
• MAO-A : peripheral, noradrenaline & 5HT
• MAO-B : central, dopamine
• Rate of MAO regeneration : 14-28 days

Monoamine Oxidase B Inhibitors
• MAO-A : peripheral, noradrenaline & 5HT
• MAO-B : central, dopamine
• Rate of MAO regeneration : 14-28 days

15

Monoamine Oxidase B Inhibitors
• Selegiline & rasagiline are both irreversible enzyme inhibitors
– Short half-life (~1.5-4hrs) but long duration of action

• Effective as monotherapy
– Early stages
– Unlike COMT inhibitors

• Not totally selective for MAO-B
• No evidence of neuroprotection

Monoamine Oxidase B Inhibitors
• Selegiline & rasagiline are both irreversible enzyme inhibitors
– Short half-life (~1.5-4hrs) but long duration of action

• Effective as monotherapy
– Early stages
– Unlike COMT inhibitors

• Not totally selective for MAO-B
• No evidence of neuroprotection

16

Monoamine Oxidase B Inhibitors
Selegiline (deprenyl, Eldepryl®, Jumex®)
• DATATOP : selegiline, vit E, placebo – Neuroprotection?? Not proven.

• _________OM to BD
• 2nd dose in the ___________
--> Hepatically metabolised to amphetamines , which
– are stimulating
– have no effect on MAO-B

Monoamine Oxidase B Inhibitors
Selegiline (deprenyl, Eldepryl®, Jumex®)
• DATATOP : selegiline, vit E, placebo – Neuroprotection?? Not proven.

• 5mg OM to BD
• 2nd dose in the afternoon
--> Hepatically metabolised to amphetamines , which
– are stimulating
– have no effect on MAO-B

17

• Rasagiline
– Not metabolised to amphetamines
– _______to _________ ____daily

• Rasagiline
– Not metabolised to amphetamines
– 0.5mg to 2mg once daily

18

Monoamine Oxidase B Inhibitors
Place in the management of PD
• Improvement in UPDRS scores not as great as with dopamine agonists or levodopa
• _____ in early stages, or ______in later stages.
• More commonly used in _________ PD

Monoamine Oxidase B Inhibitors
Place in the management of PD
• Improvement in UPDRS scores not as great as with dopamine agonists or levodopa
• Monotherapy in early stages, or adjunct in later stages.
• More commonly used in early stages of young onset PD

19

Catechol-O-Methyl Transferase inhibitors
• In the presence of a DCI, COMT = major metaboliser of levodopa
• Entacapone, tolcapone
• Decreases “off” time
• Not effective without concurrent levodopa
– In animals, shown to Inhibit central COMT activity but
– Enters the CNS minimally

Catechol-O-Methyl Transferase inhibitors
• In the presence of a DCI, COMT = major metaboliser of levodopa
• Entacapone, tolcapone
• Decreases “off” time
• Not effective without concurrent levodopa
– In animals, shown to Inhibit central COMT activity but
– Enters the CNS minimally

20

Catechol-O-Methyl Transferase inhibitors
Entacapone
• Selective, reversible COMT inhibitor
• Administration instruction

Catechol-O-Methyl Transferase inhibitors
Entacapone
• Selective, reversible COMT inhibitor
• must be taken at the same time as levodopa

21

Entacapone
• Use “with caution” in __________ impairment
• Monitoring of _________ generally not required

• Available in two forms
– Comtan® : entacapone
– Stalevo® : levodopa, carbidopa and entacapone.

Entacapone
• Use “with caution” in hepatic impairment
• Monitoring of LFTs generally not required

• Available in two forms
– Comtan® : entacapone
– Stalevo® : levodopa, carbidopa and entacapone.

22

• Tolcapone
– More ____and ____duration of effect than entacapone

• DECREASE “off time” : 2-3 hours (entacapone 1-2 hours)
• may also need a DECREASE in levodopa dose
– LFTs every _______ weeks x _____ months (initiation & after every dose increment)
– Not registered in S’pore

• Tolcapone
– More potent and longer duration of effect than entacapone

• DECREASE “off time” : 2-3 hours (entacapone 1-2 hours)
• may also need a DECREASE in levodopa dose
– LFTs every 2 to 4 weeks x 6 months (initiation & after every dose increment)
– Not registered in S’pore

23

Anticholinergics

• Limited use in PD
• In practice, primarily used to control tremor

only CNS acting anticolinergics can work
• Ipratropium • Hyoscine N-butylbromide • Tolterodine
are all peripheral acting drug

Anticholinergics

• Limited use in PD
• In practice, primarily used to control tremor

only CNS acting anticolinergics can work
• Ipratropium • Hyoscine N-butylbromide • Tolterodine
are all peripheral acting drug

24

NMDA antagonists
• NMDA = N-methyl-D-aspartate
• One of the chemicals a/w neurotoxicity is glutamate.
• Glutamate actives NMDA receptor activity which activates processes that encourage cell death.
• INCREASED Glutamatergic activity linked to the
– Development of, and
– Maintenance of levodopa-induced dyskinesias

NMDA antagonists
• NMDA = N-methyl-D-aspartate
• One of the chemicals a/w neurotoxicity is glutamate.
• Glutamate actives NMDA receptor activity which activates processes that encourage cell death.
• INCREASED Glutamatergic activity linked to the
– Development of, and
– Maintenance of levodopa-induced dyskinesias

25

NMDA antagonists
Amantadine

• Several proposed mechanisms of action
– NMDA antagonist
– Anticholinergic
– Upregulates D2 receptors, INCREASE sensitivity of D2 receptors

• Renally excreted
– reduce dose in renal imp
• Can be stimulating – 2nd dose in the afternoon, not at night

• Avoid concurrent use with memantine

NMDA antagonists
Amantadine

• Several proposed mechanisms of action
– NMDA antagonist
– Anticholinergic
– Upregulates D2 receptors, INCREASE sensitivity of D2 receptors

• Renally excreted
– reduce dose in renal imp
• Can be stimulating – 2nd dose in the afternoon, not at night

• Avoid concurrent use with memantine

26

NMDA antagonists
Amantadine
• Place in management of PD

– Adjunctive
– Managing levodopa-induced dyskinesias

27

Non-motor symptoms of PD

- neuropsychiatry

depression
anxiety/restlessness
psychosis
slow thinking
memory impairment
dementia
vivid dreams

- autonomic
sexual dysfunction
orthostatic hypotension
urinary dysfunction
constipation
drooling
drenching sweats
abdominal bloating
flatulence

- others
insomnia
excess daytime sleepiness
pain
tingling, aching limbs
seborrhea dermatitis

28

Drug-induced parkinsonism
• Usually difficult to distinguish from PD but
– Symptoms tend to occur bilaterally
– Withdrawal of the drug usually leads to improvement in symptoms in 80% of patients in 8 weeks
– Treatment should be withdrawal of offending drug

Drug-induced parkinsonism
• Usually difficult to distinguish from PD but
– Symptoms tend to occur bilaterally
– Withdrawal of the drug usually leads to improvement in symptoms in 80% of patients in 8 weeks
– Treatment should be withdrawal of offending drug

29

Medication review

• Correct levodopa preparation?
• Can the patient swallow?
• Drug interactions
• Comorbidities
– Drug-drug interactions
• e.g. depression – SSRIs (Is the patient taking selegiline?)
• E.g. BPH – alpha blockers (hypotension)
• Timing??
– Specific times of administration
– Entacapone must be taken at the same time as levodopa