Neurological Drugs Flashcards
What are causes of parkinsonsim?
• Idiopathic Parkinson’s disease - asymmetrical
• Drug induced parkinsonism
o Antipsychotics
o Methyldopa (centrally acting antihypertensive)
o Metoclopramide
• Vascular parkinsonism (infarction of basal ganglia) – sudden onset
• Progressive supranuclear palsy – symmetrical, get downward gaze disturbance
• Multiple systems atrophy – affects the autonomic nervous system and cerebellum too - symmetrical
• Corticobasal degeneration – can be asymmetrical, get cortical deficit
Describe idiopathic parkinsons disease
Idiopathic Parkinson’s Disease is a neurodegenerative disorder which has motor symptoms and non-motor symptoms. The cardinal features are: • Tremor (3-5Hz pill rolling resting tremor) • Rigidity (lead pipe + cog wheeling) • Bradykinesia • Postural instability Tremor and rigidity are due to dopamine and other neurotransmitter levels, bradykinesia is due to low dopamine alone. The non-motor manifestations include: • Mood changes • Pain • Cognitive changes • Urinary symptoms • Sleep disorder • Sweating
Describe catecholamine synthesis and breakdown
Synthesised from L-tyrosine, which is converted to l-dopa, then dopamine. In some cells it is then further converted into noradrenaline and adrenaline, but in the substantia nigra’s dopaminergic projections it remains as dopamine.
Dopamine is broken down by monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT) (in either order) with the end product being homovanillic acid.
Describe the pathophysiology of PD
Degeneration of dopaminergic projections to the striatum from the substantia nigra in the midbrain. You get Lewy bodies (similar pathology, just different location, to Lewy body dementia). Because of the loss of dopaminergic input to the striatum you get increased activity of the indirect pathway (so more inhibition of the thalamus) and decreased activity of the direct pathway (so more inhibition of the thalamus) which means movement is inhibited. Because of this lack of dopamine you can either give dopamine precursors to increase signalling from the remaining neurons, or give dopamine agonists.
What is Levodopa MOA? What is it administered with?
- Dopamine cannot cross the BBB whereas L-DOPA gets actively transported in and can be converted to dopamine once inside
- Administered with a peripheral DOPA decarboxylase inhibitor that cannot cross the BBB, therefore decarboxylation to dopamine can only occur in the CNS where we want to increase dopamine (co-careldopa or co-beneldopa) as 90% would be broken down in the gut and 9% in the peripheral tissues otherwise
Pharmacokinetics of levodopa
Oral administration – absorbed in competition with amino acids (so you can’t give with high protein meals
Without carbidopa or similar 90% is inactivated in the intestinal wall (MAO, dopa decarboxylase), and 9% converted peripherally – so less than 1% enters the CNS where again it has to compete with amino acids for active transport.
Short half life leads to fluctuations and the need for regular dosing
Addition of carbidopa or benserazide reduces the dose required and peripheral side effects.
What are the ADRs of L-DOPA?
Nausea and anorexia (acting on vomiting centres – give domperidone)
Hypotension
Psychosis – hallucination, delusion and paranoia
Tachycardia
Stops working/becomes less reliable when you run out of dopaminergic neurons – can lead to motor fluctuations - loss of efficacy in long term.
What are DDIs of L-DOPA
Pyridoxine (vitamin B6) increases peripheral breakdown
MAOIs risk hypertensive crisis
Interact with antipsychotics - can block dopamine receptors (haloperidol)
What are dopamine receptor antagonists? Mechaism of action?
Ergot derived – bromocryptine, pergolide, cabergoline
Non-ergot – ropinirole, pramipexole
Patch – rotigotine
Subcutaneous – apomorphine (if there are severe motor fluctuations)
• Direct agonise dopamine receptors
Compare Dopamine receptor antagonists and Levodopa
Less dyskinesias and motor complications than DOPA.
ADRs of dopamine receptor antagonists?
Impulse control disorders: -compulsive shopping -punding -pathological gambling -hypersexuality -desire to increase dosage Psychiatric side effects (dose limiting) - hallucinations Expense! Sedation Confusion Nausea Hypotension
Examples MOA of monoamine oxidase B inhibitors
Selegiline, rasagaline
Prevents the metabolism of dopamine by monoamine oxidase b (which predominates in dopamine containing areas of the brain), increasing dopamine levels – can be used alone or to prolong the action of L-DOPA + smooth out motor response
Example, MOA of Catechol-o-methyl transferase inhibitors
Doesn’t cross BBB - reduce peripheral breakdown of L-DOPA to 3-O-methyldopa (reducing the competition for transport into the CNS) so more enters the CNS.
No therapeutic effect without L-DOPA – “spare” it so you need a lower dose and prolongs the motor response
Example, MOA, ADRs of anticholinergics
Procyclidine
Minor role - only treats tremor
confusion, drowsiness, other anticholinergic side effects (dry mouth, blurred vision, urinary retention)
Example, MOA of amantadine
Uncertain (also an M2 inhibitor) – may enhance dopamine release, or anticholinergic
NOt great
