Neurological Pharmacology Flashcards
What are some of the key clinical features of Parkinsonism
- Tremor
- Rigifity
- Bradykinesia
- Postural instability
What are some of the non motor manifestations of Parkinsonism?
- Mood changes
- Pain
- Cognitive change
- Urinary symptoms
- Sleep disorders
- Sweating
- Swallowing problems
What is the underlying pathological basis of Parkinson’s Disease?
Low Dopamine due to loss of neurones in the substantia nigra
How is idiopathic Parkinson’s Disease diagnosed?
Based on:
- Clinical features
- Exclude other causes e.g. drug induced, vascular, progressive supranuclear palsy etc
- Responding to treatment
- Normal structural neuro imaging
Explain how a decrease in dopamine leads to the motor symptoms seen in Parkinsons
- A decrease in Dopamine leads to less inhibition on the neurostriatum
- Less inhibition = increased acetyl choline production
- Signals ot the motor cortex are altered; indirect pathway (inhibitory) is overstimulated and direct pathways (excitatory) is understimulated → reduced movement
Describe the synthesis of Dopamine
- L- Tyrosine precursor converted to L-DOPA
- L-DOPA converted to Dopamine by DOPA decarboxylase
- Further conversion turn dopamine into norepinephrine/ epinephrine
How is dopamine degraded?
Dopamine converted to Homovanillic acid via enzymes monoamine oxidase and catechol-O-methyl transferases (COMT)
What is measured on a DAT scan?
A type of PET scan measuring the re-uptake of neurotransmitters
In Parkinson’s re-uptake is reduced as there are less neurones to release neurotransmitter in the first place
Why can Parkinson’s disease not be treated by simply giving dopamine directly? What is given instead?
Dopamine cannot cross the blood brain barrier
L-DOPA is a dopamine pre-cursor that can cross the blood brain barrier (by active transport)
Why does L-DOPA start as a good treatment for Parkinson’s but then become less reliable over time?
- Levodopa needs to be taken up by dopamingergic cells in the substantia nigra to be converted to dopamine
- Over time, the number of neurones becomes less and less so the effect is not as great
Describe the pharmacokinetics if L-DOPA
- Orally administered
- 90% in inactivated in the intestinal wall due to MOA and DOPA decarboxylase
- T 1/2 of 2 hours → need frequent dosing 3-5x day
- 9% broken down peripherally by DOPA decarboxylase
- <1% enters the CNS
What should patients taking L-DOPA be mindful of when taking their medication and why?
Need to avoid meals with large protein content at the same time as taking drug
Why?: L-DOPA is taken up by active transport , amino acids from protein compete with L-DOPA and less L-DOPA can be absorbed
Why is L-DOPA used in combination with a peripheral DOPA decarboxylase inhibitor?
The DOPA decarboxylase inhibitor will reduce the amount of L-DOPA broken down in the periphery before reaching the brain
Allows for:
- Reduced doses required
- Reduced side effects
- Increased amount of L-DOPA reaching the brain
Give the name of 2 L-DOPA and DOPA decarboxylase inhibitor combinations
- Sinemet (Co-careldopa)
- Madopar (Co-beneldopa)
What are the advantages of L-DOPA to treat Parkinsonism?
- Highly efficacious
- Low side effects, the ones that do exist:
- Nausea and anorexia
- Hypotension central and peripheral
- Psychosis (hallucinations, delusion, paranoia)
- Tachycardia
How do Catechol-O-methyl transferase (COMT) inhibitors work?
- Reduce the peripheral breakdown of L-DOPA to 3-O-methyldopa
- 3-O-methydopa then comeptes with L-DOPA for active transport into CNS
- HAS NO THERAPEUTIC EFFECT ALONE - only works when given with L-DOPA and peripheral dopa decarboxylase inhibitor (Stalevo)
Explain the underlying pathology of Myasthenia Gravis
autoimmune disorder causing degredation of nicotinic acetycholine receptors on post synaptic clefts
What are some of the clinical features of myasthenia gravis?
Fluctuating, fatiguable weakness of skeletal muscle
- Extraoccular muscles- commonest presentation is double vision/ ptosis
- Bulbar involvement (speech and swallowing difficulties)- dysphagia, dysphonia, dysarthria
- Limb weakness
- Respiratory muscle involvement (diapragm)
