Neurologicall Pharmacology Flashcards
What is IPD?
Idiopathic PArkinsons disease:
• Neurodegenerative disorder - don’t know why the neurones degenerate
• Progressive clinical course - not symmetrical, one sided
• Motor symptoms improve with levodopa
• Non motor symptoms
What are the clinicl features of parkinsonism
- Tremor* - Pill rolling tremour , very small amplitude
- Rigidity* -
- cog wheel rigidity - when patients move wrist through arc, can feel cog wheeling
- lead pipe rigidity = same thoughout bend. Can have resistance, then give
• Bradykinesia** Caused by low dopamine state.
Degeration of opamine neurones
in substantia nigra low dopamine
in particular causes bradykinesia
• Postural instability
*low dopamine and disturbance
other neurotransmitter levels
**low dopamine
What are non-motor manifestations of parkinsonism
- Mood changes
- Pain
- Cognitive change - dementia
- Urinary symptoms
- Sleep disorder - rem sleep behavious disorder
- Sweating,e xcessive drooling
Describe the prognosis in PD
• 94% Dyskinesia - involuntary writhing movements caused by l-dopa
• 81% Falls - not a feature of early parkinsons
• 84% Cognitive decline (50%
hallucinations) - due to synuclein deposits which damage cells
• 80% Somnolence - exacerbated by drugs
• 50% Swallowing difficulty - a lot of drugs are oral
• 27% Severe speech problems - very very low volume
How can IPD be diagnosed
- Clinical Features
- Exclude other causes of Parkinsonism
- Response to Treatment
- Structural neuro imaging is normal
What are other causes of parkinsonism
- Drug induced PArkinsonism
- Vascular parkinsonism
- Progressive supranuclear palsy
- Multiple systems atrophy
- Corticobasal degeneration
What is a DAT scan?
- Labelled tracer
- Presynaptic uptake
- Abnormal in PD
- Not diagnostic
- Tremor
- Neuroleptic
- Vascular
Labelling ability to reuptake dopamine. Asymmetrical ii Parkinson’s . This isnt a scan
for Parkinson’s. Any conditions that damages the basal ganglia, will have abnormal
scan. These scans - if someone has a tremor - we do the scan - if it’s normal - a
tremor but for reasons that aren’t Parkinson’s if the skkan is normal. Euroleptic
drugs - tip someone to a tendency for Parkinson’s or might cause extrapyramidal
side effects. If your not sure in someone taking these drugs - ifi it’s normal, its the
drugs. If its not normal - combination of both
Describe the pathology of IPD
• Neurodegeneration • Lewy bodies – synucleinopathy • Loss of pigment – 50% loss->symptoms – Increased turnover – Upregulate receptors • Reduced dopamine
Cell bodied in substantiaa nigra - dopamnergic cells.. n PID those cells disappeared. Motor symptoms dont manifest until 50% lost. Already lost half the neurones. Need to predict so they can be treated before
Describe catecholamine synthesis
ss
Describe dopamine degradation
ss
What are drug classes used in IPD?
- Levodopa (L-DOPA)
- Dopamine receptor agonists
- MAOI type B inhibitors
- COMT inhibitors
- Anticholinergics
- Amantidine
Why is dopamine not used in IPD treatment?
does nto cross the bbb
What is L-dopa?
Levodopa must be taken up by dopaminergic cells in the substantia nigra
to be converted to dopamine. Fewer remaining cells - less reliable effect
of levodopa- motor fluctuations
Describe the PK of l-dopa
- Oral administration
- Absorbed by active transport • In competition with amino acids (NB high protein meals)
- 90% inactivated in intestinal wall • monoamine oxidase & DOPA decarboxylase
- T1/2 2 hours
• short dose interval
• fluctuations in blood levels and symptoms
• (physiologically dopamine is produced tonically)
• 9% converted to dopamine in peripheral tissues
• DOPA decarboxylase
• <1% enters CNS
• Again competes with amino acids for active transport across blood brain
barrier
What is l-dopa used in combination with and why
L-DOPA is used in combination with a peripheral DOPA decarboxylase inhibitor : • Co-careldopa - Sinemet • Co-beneldopa - Madopar • Reduced dose required • Reduced side effects • Increased L-DOPA reaching brain
How do peripheral dopa decarbocylase inhibitors work?
Inhibit peripheral dopa decarboxylase, less l-dopa metabolised
What are the formulations of L-dopa?
Tablet formulations only
– Standard dosage – variable strengths
– Controlled release preparations (CR)
– Dispersible Madopar (not soluble)
What are the advantages of L-DOPA
Advantages • Highly efficacious • Low side effects • Nausea/ anorexia – Vomiting centres • Hypotension – central and peripheral • Psychosis – Schizophrenia-like effects. Hallucination/ delusion/ paranoia • Tachycardia
Low ish side effects but may be nauseous can give anti emetic but avoid dopamine blcokers like metacloperamide. Give domperidone which one interfere.. need to get use to feeling o dizziness when they stand up can exacerbate psychiatric effect and increase hallucinations
What are the disadvantages of L-dopa?
Disadvantages
• Precursor
• needs enzyme
conversion
• Long term
• Loss of efficacy (Only effective in presence of dopaminergic neurones) • Involuntary movements • Motor Complications – On / off – Wearing off – Dyskinesias – Dystonia – Freezing
If interval is too long for
patient - if they eed bigger/
longer dose can feel need
before wearing of . Dystonia.
- overuse and underuse of l-
dopa not sure which. In
What are DDIs of L-dopa?
• Pyridoxine (vitamin B6) increases peripheral
breakdown of L-DOPA
- MAOIs risk hypertensive crisis
- (not MOABIs at normal dose-lose specificity at high dose)
• Many antipsychotic drugs block dopamine receptors
and parkinsonism is a side effect (newer, ‘atypical’
antipsychotics less so)
Wha are some examples of dopamine receptor agonists?
De Novo therapy
Add on therapy
• Non Ergot Ropinirole
Pramipexole
- Patch Rotigotine
- Subcutaneous Apomorphine - only for patients with severe motor fluctuations
No longer used:
• Ergot derived Bromocryptine
Pergolide
Cabergoline
What are advantages of DRAs?
Advantages • Direct acting - doesnt need to be converted • Less dyskinesias/ motor complications • Possible neuroprotection
What are disadvantages of DRAs?
Disadvantages • Less efficacy than L-DOPA • Impulse control disorders • More psychiatric s/e
- Dose limiting
- Expensive
What are examples of impulse control disorders?
- Pathological Gambling
- Hypersexuality
- Compulsive Shopping
- Desire to increase dosage
- Punding - collecting and storing
What are DRA side effects
- Sedation
- Hallucinations
- Confusion
- Nausea
- Hypotension
Older the patient 0 more likely
to have pd. may have slight
dementia or confusion. Dont
want to onfoun
What is monoamine oxidase B
- Monoamine oxidase B
- Metabolises dopamine
- Predominates in dopamine containing regions in brain
- MAOB inhibitors enhance dopamine
What are examples of MAOI type B inhibitors
• Monoamine oxidase B inhibitors
- Selegiline
- Rasagaline
What are the effects of MAOI-B inhibitors
- Can be used alone
- Prolong action of L-DOPA
- Smooths out motor response
- May be neuroprotective
What are COMT inhibitors
• Catechol-O-methyl Transferase (COMT)
Inhibitors
• Entacapone – doesn’t cross BBB
reduce peripheral breakdown of l-dopa
No longer used:
• Tolcapone – crosses BBB but main effect peripheral
» Monitor liver function
What are the effects of dCOMMT inhibitors
• Reduce peripheral breakdown of L-DOPA to 3-O-methyldopa
» 3-O-methyldopa competes with L-DOPA active transport into CNS
• No therapeutic effect alone
» Can use combination tablets COMT inhibitor and L-DOPA and
peripheral dopa decarboxylase inhibitor - Stalevo
• Have L-DOPA ‘sparing’ effect
• Prolongs motor response to L-DOPA
» Reduces symptoms of ‘wearing off’
Describe the usage of Anticholinergics in pd
Acetyl Choline may have antagonistic effects to
dopamine
- Trihexyphenidydyl
- Orphenadrine
- Procyclidine
• Minor role in treatment of PD
These do not affect bradykinesia and rigidity bc those are dopamine effects. But t helps with tremor.but it makes pl confused. Less beneficial effects and too many side effects to have a major role. Tremor had less impact then stiffness and slowness.
What are the advantages of anticholinergics
Advantages
• Treat tremor
• Not acting via
dopamine systems
What are the disadvanteges of anticholinergics
Disadvantages
• No effect on bradykinesia • Side effects • Confusion • Drowsiness • Usual anticholinergic s/e
What is amantadine
• Mechanism action uncertain – possibly
- enhanced dopamine release
- Anticholinergic NMDA inhibition
- Poorly effective
- Few side effects
- Little effect on tremor
what are some surgery options for PD?
- Carried out stereotactically
- Of value in highly selected cases
- Dopamine responsive
- Significant side effects with L-DOPA
- No psychiatric illness
- Controlled trials
- Lesion
- Thalamus for tremor
- Globus Pallidus Interna for dyskinesias
• Deep brain stimulation • Subthalamic nucleus Dont destroy any brain tissue. Put an electrode into subthalamic nucleus. Have to be dopamine reposnisve but nto able to take l dopa
What is Myasthenia Gravis?
• Fluctuating, fatiguable, weakness skeletal
muscle
– Extraocular muscles – commonest presentation
– Bulbar involvement – dysphagia, dysphonia, dysarthria
– Limb weakness – proximal symmetric
– Respiratory muscle involvemeng
Double vision + ptosis and weakness common and possible slurring or speech/problem
swallowing - indicates MG
O sensory involvement - post synaptic probelm. Extraoccula muscles and bulbar muscles (speech and swallowing) - pharynx and larynx — limb Double vision + ptosis and weakness common and possible
How do drugs which affect nmj affect MGtransmission
Exacerbate it • Aminoglycosides • Beta-blockers, CCBs, quinidine, procainamide • Chloroquine, penicillamine • Succinylcholine • Magnesium • ACE inhibitors
What drugs are we not going to give them. Not contraindicated but we are not going to give these. Safest thing - tell them I theyre going to start a thug tell the gp that u have MG. doesnt mean u cant abhvae it but ight interfere
What are complications of MG?
• Acute exacerbation
– Myasthenic crisis
• Overtreatment
– Cholinergic crisis
Muscles increasingly weak either secondary
to myasthenia crisis but can also be overtreatment - give ache inhibitor - ach is metabolise by esterase - leave ach there so. If oevrtert. Depolarising
block - caused by the treatment. Cant get cholinegic crisis if MG unless on a treatment
that would cause it
What is the firts line management for MG
• Acetylcholinesterase inhibitors
Describe the use of AChE inhibitors in MG
• Acetylcholinesterase inhibitors – Enhance neuromuscular transmission – Skeletal and smooth muscle – Excess dose can cause depolarising block – cholinergic crisis – Muscarinic side effects
Pyridostigmine - oral
Neostigmine – oral and IV preparations (ITU)
• Quicker action, duration up to 4 hours
• Significant antimuscarinic side effect
What is pyridostigmine
• Prevents breakdown of ACh in NMJ • ACh more likely to engage with remaining receptors • Onset 30min; peak 60-120min; duration 3-6hr • Dose interval and timing crucial • Antimuscarinic side effect – – miosis and the SSLUDGE syndrome: » Salivation, » Sweating, » Lacrimation » Urinary incontinence » Diarrhea, » GI upset and hypermotility » Emesis)
