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
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
• Rasagiline
– Not metabolised to amphetamines
– _______to _________ ____daily
• Rasagiline
– Not metabolised to amphetamines
– 0.5mg to 2mg once daily
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
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
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
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.
• 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
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
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
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
NMDA antagonists
Amantadine
• Place in management of PD
– Adjunctive
– Managing levodopa-induced dyskinesias
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
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
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
