S12) Neuropharmacology Flashcards
Identify four clinical features of Parkinsonism
- Tremor
- Rigidity
- Bradykinesia
- Postural instability
What are the non-motor manifestations of Parkinson’s disease?
- Mood changes
- Pain
- Cognitive change
- Urinary symptoms
- Sleep disorder
- Sweating
After 15 years, what clinical features will patients with PD have during follow up?
- Dyskinesia (94%)
- Falls (81%)
- Cognitive decline (84%)
- Somnolence (80%)
- Swallowing difficulties (50%)
- Severe speech problems (27%)
How does one make a diagnosis of Idiopathic Parkinson’s Disease?
- Clinical features
- Exclude other causes of Parkinsonism
- Response to treatment
- Normal structural neuro-imaging
Describe the pathological features of IPD
- Neurodegeneration
- Lewy bodies synucleinopathy
- Loss of pigment
- Reduced dopamine
Describe three ways in which the basal ganglia circuitry is affected in IPD
Identify six different drug classes used to treat IPD
- Levodopa (L-DOPA)
- Dopamine receptor agonists
- MAOI type B inhibitors
- COMT inhibitors
- Anticholinergics
- Amantidine
Why is L-DOPA used to treat IPD instead of Dopamine?
How is Levodopa administered?
Oral administration
In five steps, describe the absorption of L-DOPA
⇒ Absorbed by active transport
⇒ Competes with amino acids
⇒ Taken up by dopaminergic cells in substantia nigra to be converted to dopamine
⇒ 90% inactivated in intestinal wall
⇒ Forms monoamine oxidase & DOPA decarboxylase
Which formulation of L-DOPA is used to increase the amount that gets to the brain?
L-DOPA is used in combination with a peripheral DOPA decarboxylase inhibitor – co-careldopa / co-beneldopa
What is the half life of L-DOPA?
T1/2 = 2 hours
What are the advantages of L-DOPA?
- Highly efficacious
- Low side effects e.g. nausea, vomiting, hypotension, tachycardia, psychosis
What are the disadvantages of L-DOPA?
- Loss of efficacy (only effective in presence of dopaminergic neurones)
- Needs enzyme conversion
- Involuntary movements
- Motor complications
Describe the drug-drug interactions of L-DOPA with the following:
- Pyridoxine (Vitamin B6)
- MAOIs
- Antipsychotic drugs
- Pyridoxine: increases peripheral breakdown of L-DOPA
- MAOIs: risk hypertensive crisis
- Antipsychotic drugs: lead to parkinsonism (block dopamine receptors)
Identify some different types of dopamine receptor agonists
- Ergot derived
- Non Ergot
- Patch
- Subcutaneous
Provide two examples of non ergot dopamine receptor agonists
- Ropinirole
- Pramipexole
Provide an example of a patch dopamine receptor agonist
Rotigotine
Provide an example of a subcutaneous dopamine receptor agonist
Apomorphine
What are the advantages of dopamine receptor agonists?
- Direct acting
- Less dyskinesia / motor complications
- Possible neuroprotection
What are the disadvantages of dopamine receptor agonists?
- Less efficacy than L-DOPA
- Impulse control disorders
- More psychiatric side effects
- Expensive
Provide five examples of impulse control disorders
- Pathological gambling
- Hypersexuality
- Compulsive shopping
- Desire to increase dosage
- Punding
What are the side effects of dopamine receptor agonists?
- Sedation
- Hallucinations
- Confusion
- Nausea
- Hypotension
Describe the mechanism of action of monoamine oxidase B inhibitors
- Inhibits metabolism of dopamine by MAO
- Prolongs action of L-DOPA
- Smooths out motor response
Provide two examples of monoamine oxidase B inhibitors
- Selegiline
- Rasagaline
Describe the mechanism of action of Catechol-O-methyl Transferase (COMT) inhibitors
- Reduce peripheral breakdown of L-DOPA to 3-O-methyldopa (3-O-methyldopa competes with L-DOPA for active transport into CNS)
- Prolongs motor response to L-DOPA
Provide an example of a COMT inhibitor
Entacapone (doesn’t cross BBB)
Describe the use of anticholinergics in the treatment of PD
- Acetyl choline may have antagonistics effects on dopamine
- Minor role in treatment of PD
Provide three examples of anticholinergics
- Trihexyphenidydyl
- Orphenadrine
- Procyclidine
What are the advantages of anticholinergics?
- Treat tremor
- Not acting via dopamine systems
What are the disadvantages of anticholinergics?
- No effect on bradykinesia
- Several side effects
What are the side effects of anticholinergics
- Confusion
- Drowsiness
The mechanism action of amantadine is uncertain.
Provide some suggestions
- Enhanced dopamine release
- Anticholinergic NMDA inhibition
What are the disadvantages of amantadine?
- Poorly effective
- Few side effects
- Little effect on tremor
Illustrate the differences in the post synaptic membrane of a normal neuromuscular junction with that of one in myasthenia gravis
Describe the presentation of Myasthenia gravis
- Extraocular muscles – commonest presentation
- Bulbar involvement – dysphagia, dysphonia, dysarthria
- Limb weakness – proximal symmetric
Identify some drugs which affect the neuromuscular transmission and thus, exacerbate Myasthenia gravis
- Aminoglycosides
- Beta-blockers
- CCBs
- Quinidine
- ACE inhibitors
What are the complications of Myasthenia gravis?
- Acute exacerbation – Myasthenic crisis
- Overtreatment – cholinergic crisis
What is the therapeutic management of Myasthenia gravis?
Acetylcholinesterase inhibitors – enhance neuromuscular transmission at skeletal and smooth muscle
Provide two examples of acetylcholinesterase inhibitors
- Pyridostigmine (oral)
- Neostigmine (oral/IV)
What are the antimuscarinic side effects of acetylcholinesterase inhibitors?
- Miosis
- SSLUDGE syndrome: salivation, sweating, lacrimation, urinary incontinence, diarrhea, GI upset and hypermotility, emesis
