20 Neurodegenerative disorders Flashcards by Emma :)

20.01 DRUGS USED IN PARKINSON’S DISEASE

Levodopa (co-beneldopa, co-careldopa) - actions

relieves the symptoms of Parkinson’s disease by being decarboxylated to dopamine in the brain

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20.01 DRUGS USED IN PARKINSON’S DISEASE

Levodopa (co-beneldopa, co-careldopa) - MOA

decarboxylation of levodopa to dopamine restores some activity in the nigrostriatal pathway
given with a peripheral dopa decarboxylase inhibitor (benserazide or carbidopa), which inhibits levodopa decarboxylation outside the brain
this allows the use of smaller doses and reduces peripheral side effects of dopamine

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20.01 DRUGS USED IN PARKINSON’S DISEASE

Levodopa (co-beneldopa, co-careldopa) - abs/distrib/elim

given orally
levodopa half-life is 1-2h when co-administered with carbidopa

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20.01 DRUGS USED IN PARKINSON’S DISEASE

Levodopa (co-beneldopa, co-careldopa) - clinical use

first-line treatment in Parkinson’s disease
more effective against akinesia and rigidity than against tremor
effectiveness diminishes over some months to a few years

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20.01 DRUGS USED IN PARKINSON’S DISEASE

Levodopa (co-beneldopa, co-careldopa) - adverse effects

anorexia, nausea and vomiting
postural hypotension
hallucinations, daytime somnolence
more slowly developing effects: dyskinesia (in most patients after 2 years) and ‘on-off’ effects (rapid fluctuations between dyskinesia and hypokinesia/rigidity)
peripheral neuropathy

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20.01 DRUGS USED IN PARKINSON’S DISEASE

Levodopa (co-beneldopa, co-careldopa) - special notes

sudden withdrawal may cause neuroleptic malignant syndrome

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20.02 DRUGS USED IN PARKINSON’S DISEASE

Dopamine agonists: pramipexole, ropinirole, rotigotine, pergolide, apomorphine - actions

direct stimulation of post-synaptic dopamine receptors

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20.02 DRUGS USED IN PARKINSON’S DISEASE

Dopamine agonists: pramipexole, ropinirole, rotigotine, pergolide, apomorphine - MOA

two main types of dopamine agonists: ‘ergot’ agonists (have an ergoline structure) and ‘non-ergot’ agonists
non-ergot agonists are D2/3 selective and stimulate striatal dopamine receptors
ergot agonists have potent and long-lasting dopamine D2 receptor agonist properties
in addition, cabergoline exerts a central dopaminergic effect via D2 receptor stimulation

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20.02 DRUGS USED IN PARKINSON’S DISEASE

Dopamine agonists: pramipexole, ropinirole, rotigotine, pergolide, apomorphine - abs/distrib/elim

given orally
short plasma half-life (6-8h), requiring three times daily dosing
slow-release (once a day) formulations are now available
rotigotine is given via transdermal patch
apomorphine can be given via SC injection or continuous SC infusion via an external pump

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20.02 DRUGS USED IN PARKINSON’S DISEASE

Dopamine agonists: pramipexole, ropinirole, rotigotine, pergolide, apomorphine - clinical use

motor symptoms of Parkinson’s disease
apomorphine is used in advanced Parkinson’s disease

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20.02 DRUGS USED IN PARKINSON’S DISEASE

Dopamine agonists: pramipexole, ropinirole, rotigotine, pergolide, apomorphine - adverse effects

rarely show the same long-term effects of levodopa (dyskinesia, ‘on-off’ fluctuations)
ergot agonists (especially pergolide) are associated with fibrosis (lung, heart, retroperitoneum) and need cardiorespiratory monitoring
nausea and vomiting
sleep disturbances
impulse control disorders
haemolytic anaemia is a rare adverse effect of apomorphine infusion

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20.03 DRUGS USED IN PARKINSON’S DISEASE

Catechol-O-methyl transferase (COMT) inhibitors: entacapone, tolcapone - actions

synergises with the antiparkinsonian effects of levodopa/carbidopa
potentiates actions of catecholamines

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20.03 DRUGS USED IN PARKINSON’S DISEASE

Catechol-O-methyl transferase (COMT) inhibitors: entacapone, tolcapone - MOA

reversible inhibition of COMT in the periphery reduces levodopa breakdown (like peripheral dopa decarboxylase inhibitors) allowing more of levodopa dose to penetrate the brain

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20.03 DRUGS USED IN PARKINSON’S DISEASE

Catechol-O-methyl transferase (COMT) inhibitors: entacapone, tolcapone - abs/distrib/elim

given orally
short half-life (1h) necessitates dosing several times/day

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20.03 DRUGS USED IN PARKINSON’S DISEASE

Catechol-O-methyl transferase (COMT) inhibitors: entacapone, tolcapone - clinical use

adjunct to levodopa/carbidopa therapy - especially for patients showing ‘end-of-dose’ symptoms (no antiparkinsonian effect by itself)

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20.03 DRUGS USED IN PARKINSON’S DISEASE

Catechol-O-methyl transferase (COMT) inhibitors: entacapone, tolcapone - adverse effects

exacerbates adverse effects of levodopa/carbidopa taken at the same time
dyskinesia, nausea, diarrhoea
postural hypotension
hallucinations
anxiety and sleepiness

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20.04 DRUGS USED IN PARKINSON’S DISEASE

Monoamine oxidase (MAOB) inhibitors: selegiline, rasagiline - actions

prevent breakdown of dopamine in synapses

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20.04 DRUGS USED IN PARKINSON’S DISEASE

Monoamine oxidase (MAOB) inhibitors: selegiline, rasagiline - MOA

selective irreversible inhibition of MAOB, the isozyme which has dopamine as a preferred substrate
potentiates action of endogenous dopamine and dopamine formed from administered levodopa

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20.04 DRUGS USED IN PARKINSON’S DISEASE

Monoamine oxidase (MAOB) inhibitors: selegiline, rasagiline - abs/distrib/elim

given orally (but low bioavailability)
half-lives: selegiline 2h, rasagiline 3h

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20.04 DRUGS USED IN PARKINSON’S DISEASE

Monoamine oxidase (MAOB) inhibitors: selegiline, rasagiline - clinical use

adjunct to levodopa/carbidopa, as their effect wanes, in Parkinson’s disease
irreversible nature of MAO inhibition prolongs effects of drug for some days
also approved for major depression

20.04 DRUGS USED IN PARKINSON’S DISEASE

Monoamine oxidase (MAOB) inhibitors: selegiline, rasagiline - adverse effects

adverse effects mainly due to increased action of levodopa taken concurrently: nausea, dyskinesia, depression, insomnia, postural hypotension, hallucinations, confusion
if dose >10 mg, selegiline can block MAOA - the enzyme involved in the metabolism of tyramine-containing foods (cheese, red wine) which can result in hypertensive crisis
severe interactions may occur with tricyclic and SSRI antidepressants

20.05 DRUGS USED IN PARKINSON’S DISEASE

Antiviral agent: amantadine - actions

anti-dyskinetic drug, originally developed as an antiviral

20.05 DRUGS USED IN PARKINSON’S DISEASE

Antiviral agent: amantadine - MOA

thought to act by increasing dopamine release from nerve endings in striatum
antimuscarinic actions, like those of benztropine, may also contribute
more recently, block of NMDA receptors by stabilising closed states of the channel has been described

20.05 DRUGS USED IN PARKINSON’S DISEASE

Antiviral agent: amantadine - abs/distrib/elim

given orally
mostly excreted unchanged in urine
half-life 17h

20.05 DRUGS USED IN PARKINSON'S DISEASE Antiviral agent: amantadine - clinical use

Parkinson’s disease generally less effective than levodopa, dopamine agonists or MAOB inhibitors effective against the dyskinesia associated with levodopa therapy (antiviral action is used for influenza infection)

20.05 DRUGS USED IN PARKINSON'S DISEASE Antiviral agent: amantadine - adverse effects

nausea, dizziness, insomnia postural hypotension anxiety, confusion, hallucinations antimuscarinic action is important contributor to death from overdose

20.06 DRUGS USED IN PARKINSON'S DISEASE Centrally acting muscarinic antagonists: benztropine, trihexyphenidyl, orphenadrine, procyclidine - actions

to treat tremor in Parkinson’s disease

20.06 DRUGS USED IN PARKINSON'S DISEASE Centrally acting muscarinic antagonists: benztropine, trihexyphenidyl, orphenadrine, procyclidine - MOA

reduces muscarinic actions of acetylcholine in striatum (restores ‘balance’ between dopaminergic and cholinergic activities) action is probably on M1 receptors

20.06 DRUGS USED IN PARKINSON'S DISEASE Centrally acting muscarinic antagonists: benztropine, trihexyphenidyl, orphenadrine, procyclidine - abs/distrib/elim

orally active half-lives: benztropine ~36h, trihexyphenidyl 3-4h

20.06 DRUGS USED IN PARKINSON'S DISEASE Centrally acting muscarinic antagonists: benztropine, trihexyphenidyl, orphenadrine, procyclidine - clinical use

now rarely used for Parkinson’s disease much less effective than those drugs increasing dopaminergic transmission, but has value in treating tremor used in antipsychotic-induced parkinsonism and acute dykinesias

20.06 DRUGS USED IN PARKINSON'S DISEASE Centrally acting muscarinic antagonists: benztropine, trihexyphenidyl, orphenadrine, procyclidine - adverse effects

confusion - best avoided in older patients effects due to parasympathetic block: dry mouth, inhibition of peristalsis, raised intraocular pressure (avoid in narrow-angle glaucoma), blurred vision, urinary retention, tachycardia, etc.

20.07 DRUGS USED IN ALZHEIMER'S DISEASE Cholinesterase inhibitors: donepezil, rivastigmine, galantamine - actions

ameliorate symptoms of Alzheimer’s disease

20.07 DRUGS USED IN ALZHEIMER'S DISEASE Cholinesterase inhibitors: donepezil, rivastigmine, galantamine - MOA

reversible inhibition of acetylcholinesterase enhance cholinergic transmission in the cerebral cortex and hippocampus

20.07 DRUGS USED IN ALZHEIMER'S DISEASE Cholinesterase inhibitors: donepezil, rivastigmine, galantamine - abs/distrib/elim

orally active half-lives: donepezil 70h, rivastigmine 1.5h, galantamine 7h

20.07 DRUGS USED IN ALZHEIMER'S DISEASE Cholinesterase inhibitors: donepezil, rivastigmine, galantamine - clinical use

mild to moderate Alzheimer’s disease provide limited relief from the symptoms but have no effect on disease progression

20.07 DRUGS USED IN ALZHEIMER'S DISEASE Cholinesterase inhibitors: donepezil, rivastigmine, galantamine - adverse effects

predictable parasympathomimetic side effects: nausea, vomiting, diarrhoea, bradycardia (baseline ECG required), increased gastric acid secretion anorexia with weight loss and insomnia also occur

20.08 DRUGS USED IN ALZHEIMER'S DISEASE N-methyl-D-aspartate (NMDA) receptor antagonist: memantine - actions

originally developed as an antiviral drug potential inhibitor of excitotoxicity

20.08 DRUGS USED IN ALZHEIMER'S DISEASE N-methyl-D-aspartate (NMDA) receptor antagonist: memantine - MOA

open-channel block of NMDA receptors prevents Na+ and, more importantly, Ca2+ entry into the neuron, so reducing glutamate excitotoxicity normal glutamatergic transmission continues

20.08 DRUGS USED IN ALZHEIMER'S DISEASE N-methyl-D-aspartate (NMDA) receptor antagonist: memantine - abs/distrib/elim

given orally half-life 60-80h

20.08 DRUGS USED IN ALZHEIMER'S DISEASE N-methyl-D-aspartate (NMDA) receptor antagonist: memantine - clinical use

moderate to severe Alzheimer’s disease provides only symptomatic relief of the cognitive and memory impairment of the disease no effect on the degenerative process can be used in combination with centrally acting anticholinesterases

20.08 DRUGS USED IN ALZHEIMER'S DISEASE N-methyl-D-aspartate (NMDA) receptor antagonist: memantine - adverse effects

usually well tolerated confusion, dizziness, drowsiness, headache, insomnia, agitation, hallucinations

20.09 DRUGS USED IN MULTIPLE SCLEROSIS Glatiramer acetate - multiple sclerosis

interferes with immune response to myelin given by SC injection reduces relapses

20.09 DRUGS USED IN MULTIPLE SCLEROSIS Dimethyl fumarate - multiple sclerosis

given orally reduces relapse rate and slows progression

20.09 DRUGS USED IN MULTIPLE SCLEROSIS Fingolimod - multiple sclerosis

inhibits cytotoxic CD8-expressing T cells given orally reduces relapse rate, but increases risk of progressive multifocal leukoencephalopathy (PML) and ventricular arrhythmias

20.09 DRUGS USED IN MULTIPLE SCLEROSIS Beta-interferons - multiple sclerosis

modulate immune response given by SC or IM injection reduces relapse rate

20.09 DRUGS USED IN MULTIPLE SCLEROSIS Natalizumab - multiple sclerosis

monoclonal antibody (α4-integrin) IV infusion (monthly) slows progression of disability in relapsing MS can cause PML

20.09 DRUGS USED IN MULTIPLE SCLEROSIS Alemtuzumab - multiple sclerosis

monoclonal antibody (CD52) IV infusion

20.09 DRUGS USED IN MULTIPLE SCLEROSIS Ocrelizumab - multiple sclerosis

monoclonal antibody (CD20) IV infusion