Drugs In Neurological Disorder Flashcards
What are the clinical features of Parkinson’s disease
Motor: Bradykinesia Rigidity Tremor Postural instability
Non-motor: Mood changes Cognitive dysfunction Urinary incontinence R.E.M. Sleep behavioural disorder
What is the pathophysiology of PD
Lewy bodies
Progressive degeneration of dopaminergic neurones in subtantia nigra pars compacta
Reduced dopamine levels
What is the metabolism pathway of dopamine
L-tyrosine to L-dopa
L-dopa to dopamine by DOPA decarboxylase
Dopamine to metabolites by COMT+MAO
Or synthesise Noradrenalin then Adrenalin
What are the medications used in PD
Levodopa Dopamine receptor agonist MAOBI COMTI Anticholinergics
What is management pathway of PD
GP suspects PD Referral to specialist for diagnosis Wait for significant disability 1. Levodopa / Dopamine receptor agonist 2. Consider CR Levodopa, agonist, Entacarpone / CR Levodopa, Entacarpone 3. Consider Surgery, Amorphine
What is the mechanism of action of Levadopa
Levadopa is prodrug because Dopamine cannot Cross BBB
Levadopa crosses BBB
Taken up by dopaminergic neurones in brain
Metabolised to dopamine intracellularly by DOPA decarboxylase
What must Levadopa be prescribed with
DOPA decarboxylase inhibitor
Inhibit Dopa decarboxylase in periphery
Prevent breakdown of Levadopa in periphery
Thus increased uptake of levodopa in CNS
Allows: less side effects, reduced dosing
What are PK properties of Levodopa
Oral admin only
Taken up by Active transport - compete with AA
90% inactivated in GIT - COMT, MAO
9% converted in periphery - DOPA decarboxylase
<1% taken up into CNS - active transport at BBB competing w AA
T1/2 2hours - short dose interval
Give examples of Levadopa
Co-careldopa: Sinemet
Co-beneldopa: Madopar
What are side effects of Levadopa
N+V (vomiting centre is dopaminergic)
Psychosis
Hypotension
Tachycardia
What happens with long term use of Levodopa
Loss of efficacy - only efficacious in presence of dopaminergic neurones Gives rise to motor complications: On/off oscillations Dyskinesia Dystonia Freezing End-of-dose deterioration in function
What are DDIs of Levodopa
Vitamin B6 (Pyridoxine): increase peripheral breakdown of Levodopa Anti-psychotic Drugs: blocks dopamine receptors MAOIs: hypertensive crisis
What are the pros and cons of Levodopa
Pros: most efficacious for motor symptoms, low SE profile
Cons: pro drug requiring metabolism, loss of efficacy long term
What are types of formulations of Levodopa
All tablet formulations:
Standard dosage
Controlled release
Dispersible Madopar
Give examples of Dopamine Receptor Agonists
Non-ergot derived: Ropinirole, Pramipexole
Patch: Rotigotine
SC: Amorphine - for severe motor fluctuations
What are indications of Dopamine receptor agonists
De-novo therapy
Add-on therapy
Severe motor fluctuations - Amorphin
What are pros and cons of Dopamine Receptor Agonists
Pros: no metabolism required, less motor complications w disease progression
Cons: less efficacious, serious SEs (impulse control disorder, more psychosis)
What are side effects of Dopamine receptor agonists
Hypotension Sedation Psychosis Paranoia Impulse control disorder: pathological gambling, hyper sexuality - check Hx of obsessive behaviour
What is mechanism of action of MAOBIs
Inhibit MAO Type B present in dopaminergic neurones
Inhibit breakdown of Dopamine
Enhance Dopamine levels
Give examples of MAOBI
Selegiline
Rasagaline
What are pros and cons of MAOBI
Pros: can be used alone, prolongs Levodopa action, allow reduced Levodopa dosage, smooth out motor fluctuations
Cons: low efficacy
What is mechanism of action of COMTI
COMTI cannot Cross BBB
Inhibit COMT in periphery
Inhibit breakdown of Levadopa in periphery into 3MO
Reduced 3MO competing for active transport at BBB
Increased CNS uptake of Levodpa
Give examples of COMTIs
Entacarpone
What are indications of COMTI
Add on therapy only:
Must be prescribed with levodopa + Dopa decarboxylase inhibitor
Allows reduced Levodopa dosing
Prolongs motor response to Levodopa
