Neurology Clinical Pharmacology Flashcards
What is idiopathic parkinson’s disease?
neudegenerative disorder
Progressive clinical course
Motor symptoms improve with levodopa
Non-motor symtoms
What are the clinical features of Parkinsonism?
Tremor - low frequency, pill rolling tremor
Rigidity - lead pipe rigidity
Bradykinesia
Postural instability
What are the non motor manifestations of parkinson’s?
Mood changes Pain - starts asymmetrical Cognitive change Urinary change Urinary symptoms Sleep disorder - REM sleep behaviour disorder Sweating
What is the prognosis of PD after 15 years?
94% dyskinesia 81% falls 84% cognitive decline - 50% hallucinations 80% somnolence 50% swallowing difficulty 27% severe speech problems.
How do you diagnose ID?
Clinical features
Exclude other causes of Parkinsonism
Response to Treatment
Structural neuroimaging is normal
Describe the pathology of IPD?
Neurodegeneration
Lewy bodies - synucleinopathy
Loss of pigment - 50% loss before symptoms, increased turnover, upregulate receptors
Reduced dopamine
What is a DAT scan?
Labelled tracer Presynaptic uptake Abnormal in PD Not diagnostic Tremor Neuroleptic Vascular
Describe the synthesis of catecholamines
L-Tyrosine (tyrosine hydroxylase) L-DOPA (DOPA decarboxylase) Dopamine (Dopamine B-Hydroxylase) Noradrenaline (Phenylethanolamine n-methyltransferse) Adrenaline
Why do we use L-DOPA and not dopamine?
As Dopamine cannot cross BBB
Describe the pharmacokinetics of levodopa
Oral administration
absorbed by AT - in competition with amino acids
90% inactivated in intestinal wall (monoamine oxidase and DOPA decarboxylase)
T1/2 = 2 hours so:
-Short dose internal (4x day)
fluctuations in blood levels and symptoms
9% converted to dopamine in peripheral tissues - DOPA decarboxylase
<1% enters CNS - competes with AA for AT across BBB.
What are the formulations of L-DOPA?
Dopamine is used in combination with a peripheral DOPA decarboxylase inhibitor:
- Co-careldopa = Sinemet
- Co-beneldopa = Madopar
This reduces the dosing required
Reduces side effects
Increases L-DOPA reaching the brain
Tablets only - standard dosage of variable strengths.
What are the advantages of L-DOPA?
Highly efficacious
Low side effects:
Nausea / anorexia - vomiting centres
Hypotension - central and peripheral
Psychosis - schizophrenia like effects - hallucinations / delusions / paranoia
Tachycardia
What are the disadvantages of L-DOPA?
Precursor - needs enzyme conversion
Long term - loss of efficacy Involuntary movements Motor complications: On/Off Wearing off - need before next dose Dyskinesias Dystonia Freezing
What are the interactions with L-DOPA?
B6 increases peripheral breakdown of L-DOPA
MAOIs risk hypertensive crisis
Many antipsychoticdrigs block dopamine receptors and parkinsonism is a side effect
What are dopamine receptor agonists?
A do novo, add on therapy.
e.g. Ropinirole, pramipexole (tablet), apomorphine (subcut, only for patients with severe motor fluctuations)
What are the advantages of DRAs?
Direct acting
Less dyskinesias / motor complications
Possible neuroprotection
What are the disadvantages of DRAs?
Less efficacy than L-DOPA
Impulse control disorders
More psychiatric s/e dose limiting
Expensive
What are impulse control disorders?
Pathological gambling Hypersexuality Compulsive shopping Desire to increase dosage Punding
What are the side effects of dopamine receptor agonists?
Sedation Hallocinations Confusion Nausea Hypotension
How does monoamine oxidase B work?
Metabolises dopamine
Predominates in dopamine containing regions in brain
MAOBi enhance dopamine.
What are some examples of Monoamine oxidase B inhibitors?
Selegiline
Rasagaline
Monoamine oxidase B inhibitors work?
Can be used alone or to prolong the action of L-DOPA.
Smooths out motor response
May be neuroprotective
How do COMT inhibitors work?
It reduces the peripheral brakdown of L-DOPA to 2-O-Mythyldopa.
Only work with L-DOPA
Have an L-DOPA ‘sparing’ effect - it prolongs the motor response to L-DOPA and reduces the symptoms of ‘weaning off’
e.g. Entacapone - called ‘Stalevo’ when combined.
Give examples of anticholinergics
Trihexyphenidydyl
Orphenadrine
Procyclidine
What are the advantages of anticholinergics?
Treat tremor
Not acting via dopamine system
What are the disadvantages of anticholinergics?
No effect on bradykinesia
Side effects:
- Confusion
- Drowsiness
- Usual anticholinergics/e
What is amantadine?
Mechanism of action uncertain maybe enhanced dopamine release or anticholinergic NMDA inhibition.
Poorly effective
Few side effects
Little effect on tremor
What surgery can be used in Parkinsons?
Of value in highly selected cases - people who are dopamine responsive but have significant side effects with L-DOPA and o psychiatric illness.
Controlled trials
Lesion -thalamus for tremor and Globus Pallidus for dyskinesias
Deep Brain Stimulation - Subthalamic Nucleus
What is Myasthenia Gravis?
Myasthenia gravis is a chronic autoimmune disease that affects neuromuscular signalling.
ACh is prevented from binding due to IgG at the receptor and so ACh is broken down by cholinesterase’s
Fluctuating fatiguability, weakness skeletal muscle
Extraocular muscles - commonest presentation
Bulbar involvement - dysphagia, dysphonia, dysarthria
Limb weakness - proximal symmetric
Respiratory muscle involvement
What drugs exacerbate Myasthenia Gravis?
Drugs affecting neuromuscular transmission exacerbate Myasthenia Gravis.
Aminoglycosides Beta-blockers, CCBs, quinidine, procainamide Chloroquinine, penicillamine Succinylcholine Magnesium ACE inhibitors ... lots more too!
What can cause a crisis?
Acute exacerbation - Myasthenia crisis
Over-treatment - cholinergic crisis
Look exactly the same.
Treat by supporting respiration and swelling immediately.
What drugs can be used to manage MG?
Acetylcholinesterase inhibitors
Corticosteroids - decrease immune response
Steroidsparing - Aathioprine
IV immunoglobulin
Plasmapheresis - removed AChR antibodies and short-term improvement.
What do acetylcholinesterase inhibitors do?
Enhance neuromuscular trasnmission
Skeletal and smooth muscle
Excess dose can cause depolarising block - cholinergic crisis
Muscarinic side effects
What is Pyridostigmine?
An anticholinergic.
It is taken orally.
Prevents breakdown of ACh in NMJ which makes ACh more likely to engage with remaining receptors.
Onset: 30mins, Peak: 60-120mins, Duration: 3-6hours.
Dose interval and timing is crucial.
What are the side effects of pyridostigmine?
Miosis and the SSLUDGE syndrome: Salivation Sweating Lacrimation Urinary incontinence Diarrhoea GI upset Emesis
What is neostigmine?
An anticholinergic
Oral and IV preparations.
Quicker action, duration up to 4 hours.
BUT, significant antimuscarinic side effects.
