Drugs Flashcards
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
• 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
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
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
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
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
Levodopa – sustained release forms INDICATION
• Useful for stiffness on waking
–> DECREASE Stiffness on waking
- Sinemet SR – X crush
- Madopar HBS – X open capsule
Dopamine agonists
• Ergot derivatives
– Bromocriptine
– Cabergoline
– Pergolide
• Non-Ergot derivatives – Ropinirole – Pramipexole – Rotigotine (transdermal) – Apomorphine (subcut)
transdermal patch
Rotigotine –> non-ergot derivatives dopamine agonists
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
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
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
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.
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
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