23. Drugs Used In Neurological Disorders Flashcards
What is meant by idiopathic Parkinson’s disease (IPD)?
- cause is unknown
- also known as ‘parkinsons’
- most common type of Parkinsonism
- neurodegenerative disorder
What are the clinical features of Parkinsonism?
Mnemonic: TRAP (patients trapped in their poorly mobile body)
1) Tremor: pill rolling, resting tremor. Abolished by movement. Usually unilateral (later can be bilateral)
2) Rigidity: cog-wheel rigidity (other form is lead pipe)
3) Akinesia/bradykinesia: slowing down and loss of spontaneous automatic movements. Hypomimia, micrographia, hypophonia, drooling
4: Postural instability: impaired balance so patients fall over easily.
Describe the non motor manifestations of parkinsons
- mood changes: depression,anxiety
- pain
- frequency of micturition
- sleep disorders: REM sleep disorder, violent + vidid dreams
- sweating
What is the prognosis of PD?
- drugs can help but the degeneration of the brain will continue
- dyskinesia
- falls (shouldn’t fall in early parkinsons)
- hallucinations
- swallowing difficulty
- somnolence
Name some other causes of Parkinsonism (i.e. differentials for IPD)
Mnemonic: VODKA
V: Vascular events e.g. stroke, MI
O: orthostatic hypotension and atonic bladder (look for multi system organ failure)
D: dementia and vertical gaze paralysis (consider supranuclear palsy)
K: Kayser-Fleisher ring (consider Wilson’s disease)
A: apraxia gait (communicating hydrocephalus)
What are the parkinsons plus disorders?
- Respond poorly to the standard treatments for Parkinson disease
- Often have a poor prognosis with faster rate of progression and death
5 Separate syndromes:
1. Multiple system atrophy (MSA)
2. Progressive supranuclear palsy (PSP)
3. Parkinsonism-dementia-amyotrophic lateral sclerosis complex
4. Corticobasal ganglionic degeneration (CBD)
5. Dementia with Lewy bodies (DLB)
Clinical Features: - Early onset of dementia
- Early onset of postural instability
- Early onset of hallucinations or psychosis
- Early autonomic symptoms: postural hypotension and urinary incontinence
- Ocular signs
What is a DAT scan?
- labelled tracer looking at pre synaptic uptake of dopamine
- if dopaminergic neurones disappear dont see as much
This is not a test for Parkinson’s however. Though it is abnormal in parkinsons
Describe the pathology of IPD?
- neurodegeneration
- reduced dopamine
- Lewy bodies (synucleinopathy)
- loss of pigment
Normally, dopamine has an inhibitory effect on ACh. What happens if you lose dopamine?
- more ACh activity
- ACh will then stimulate GABA which is inhibitory
- this causes slowness of movement
How is dopamine synthesised?
- synthesised from L-Tyrosine
- then L-DOPA
- then dopamine
- then noradrenaline
- then adrenaline
The enzyme that converts L-DOPA to dopamine is DOPA decarboxylase
How is dopamine degraded?
- dopamine is eventually degraded to homovanillic acid
The major enzymes involved are: - Monoamine oxidase and aldehyde dehydrogenase
*Catechol-O-methyl transferase
The 2 intermediates are:
3-methoxytyramine
3,4 dihydrophenol acetic acid
Name the drug classes which can be used in IPD?
- Levodopa (L-Dopa)
- Dopamine receptor agonists
- MAO type B inhibitors
- COMT inhibitors
- Anticholinergics
How does L-dopa work?
- taken up by dopaminergic neurones into the substantia nigra
- converted into dopamine
- this is why if there’s no dopaminergic neurones left then it wont be able to work
- so as disease progresses the treatment doesn’t work as well
What food should be avoided when taking L-Dopa?
- protein rich e.g. steaks
- because it can be antagonised by amino acids
- in competition with vitamin B6
Discuss the pharmacokinetics of L-Dopa focussing on half life and bioavailability
- taken orally
- short half life 2hrs
- 90% inactivated in intestinal wall
- 9% that has been absorbed is converted to D2 in peripheral tissues
- so less than 1% enters the CNS
Need strategies to preserve it
What do we give L-DOPA in combination with? Give 2 examples
A peripheral DOPA decarboxylase inhibitor
Co-careldopa- Sinemet
Co-beneldopa - Madopar
This allows us to reduce the dose, so less side effects and increased L-DOPA reaching the brain
What are the side effects of L-DOPA?
- nausea and vomiting (can give domperidone)
- hypotension
- tachycardia
- hallucinations/delusions and paranoia
What are the long term motor complications of giving the drug L-DOPA?
- on/off, wearing off
- freezing
- dystopia
- dyskinesia
What are the potential interactions of L-DOPA with other drugs?
- Pyridoxine (vitamin B6) increases the peripheral breakdown of L-DOPA
- MAOIs: risk of hypertensive crisis
Many antipsychotics block dopamine receptors resulting in Parkinsonism as a side effect so check their other drugs.
Name some dopamine receptor agonist (both ergot and non ergot)
Ergot: bromocriptine, cabergoline
Non-ergot: Ropinirole
Patch: rotigotine - good for those that can’t take it orally
In patients with severe motor fluctuations can give apomorphine as rescue medication.
What are the advantages of dopamine receptor agonists?
- direct acting and don’t require dopaminergic neurones to be in place
- less motor complications
- possible neuroprotection
What are the disadvantages of dopamine receptor agonists?
- less efficacy then L-dopa
- impulse control disorders: hyper sexuality, gambling, compulsive shopping
- more psychiatric side effects e.g. hallucinations, confusion
- nausea, hypotension
How do MAOI work?
- normally monoamine oxidase metabolises dopamine
- if you inhibit it you will enhance dopamine
- can be used alone or to prolong action of L-DOPA
Give 2 examples of MAOI’s?
- selegiline
- rasagiline
How do COMT inhibitors work?
- no therapeutic effect alone
- given in combination with L-DOPA
- this prevents peripheral breakdown of L-DOPA to 3-0-methyldopa
- this allows more L DOPA to get into the CNS
- because normally 3-0 methyldopa competes with L-DOPA for entry into CNS
Give 2 examples fo COMT Inhibitors.
Entacapone
Tolcapone
What are anticholinergics useful for treating? Examples
- tremor predominant parkinsons
- doesn’t treat bradykinesia
- procyclidine
- Orphenadrine
Will get usual anticholinergics side effects
What is amantadine?
- thought too enhance dopamine release but mechanism uncertain
- poorly effective so hardly used
- used in fatigue and MS
In which parkinsons patients can we use surgery?
- only dopamine responsive patients
- must have had side effects to drugs
- no psychiatric illness, must be screened as there can be depression post surgery
What do we target in surgery for parkinsons?
Thalamus: for tremor (T for T)
Globus pallidus interna for dyskinesias
Deep brain stimulation: subthalamic nucleus
What is myasthenia gravis?
- autoimmune disease
- antibodies are produced to the ACh receptors at the NMJ
- cant get ACh in which will lead to fluctuating, faiguable weakness at the skeletal muscles
Name the signs seen in myasthenia gravis
- Extraocular muscles: ptosis and diplopia
- Bulbar involvement - dysphagia, dysphonia, dysarthria
- Limb weakness
- respiratory muscle involvement
May see frontalis overactivity and the eyelid may come down over the pupil which can only happen in MG cannot do voluntarily
What drugs actually make myasthenia gravis worse?
This drugs which affect neuromuscular transmission:
E.g. magnesium Succinylcholine Beta blockers, CCBs ACE inhibitors Aminoglycosides
What classes of drugs can be used to treat myasthenia gravis?
- Acetylcholinesterase inhibitors e.g. pyridostigmine and neostigmine to treat symptoms
- corticosteroids e.g. azathioprine decrease immune response
- IV immunoglobulin : for acute decline or crisis
- plasmapheresis: removes AChR antibodies (short term improvement)
What are the antimuscarinic side effects of pyridostigmine and neostigmine?
Mnemonic: SSLUDGE
Drugs like pyridostigmine are very effective as they prevent breakdown of ACh in NMJ so ACh is more likely to engage with the remaining receptors and so patients may take too much of it and it can lead to cholinergic crisis whereby we get anti-muscarinic side effects: miosis and SSLUDGE:
S: salivation S: sweating L: lacrimation U: urinary incontinence D: diarrhoea G: GI upset and hyeprmotility E: Emesis
What directions must be given regarding acetylcholinesterase inhibitors e.g. pyridostigmine?
- 30-40 mins before meals
- require close monitoring if bulbar symptoms
- before giving give 1/10th dose to see if they have a cardiac reaction
