Lecture 24- Neuropharmacology Flashcards
Idiopathic Parkinson’s disease (IPD)
- Neurodegenerative disorder
- Progressive clinical course
- Motor symptoms improve with levodopa (symptomatic medication)
- Non motor symptoms
Pathophysiology of IPD
- Degeneration of dopaminergic neurones present in substantia nigra
- If we remove dopamine provided by the SN, then we lose net excitation on the cortex (dopamine stimulates direct pathway (which increases movement)and inhibits indirect pathway (which decreases movement))
- Therefore cortical activity decreases- corticospinal pathways aren’t stimulating LMN adequately
- Tremor
- Rigidity- reduction in proper coordination in flexors and extensors
- Bradykinesia- most easily explained by this pathway
- Psychiatric features- cognition circuit interlinked with the basal ganglia circuit
Histological hallmarks
basal ganglia rev
Clinical features of parkinsonism
- Tremor*
- Rigidity*
- Bradykinesia**
- Postural instability
Non motor manifestations
- Mood changes
- Pain
- Cognitive change
- Urinary symptoms
- Sleep disorder
- Sweating
- Low Blood Pressure
- Restless legs
- Fatigue
- Hallucinations
Diagnosis of IPD (based on clinical opinion and not on tests)
- Clinical Features
- Exclude other causes of Parkinsonism
- Response to Treatment e.g. Levadopa
- Structural neuro imaging is normal
prognosis
Catecholamine synthesis
one way to target low dopamine is
to prevent its degradation
e.g. COMT or MAO inhibitors
outline neurotransmission starting at synthesis of NT e.g. dopamine
AP causes releases into synaptic cleft via action of calcium which causes vesicle docking
treatment of parkinsons disease
- symptomatic e.g. movement disorders and non motor feautres
- levodopa (LDOPA)
- dopamine receptor agonists
- MAOI type B inhibitors
- COMT inhibitors
- anticholinergics
- amatidine
- Neuroprotection
- surgery
Why use precursor Levodopa (L-dopa)and not dopamine?
- Dopamine cannot cross the BBB
- Also causes many peripheral side effects
- Irregular beart beat
- Anxiety
- Headache
- SoB
- Nausea
Levodopa
is a drug used in combination with a peirpheral DOPA decarboxylase inhibitor e.g. carbidopa or benserazide
- reduces dose required
- reduces side effects
- increase L-DOPA reaching the brain
co-careldopa
sinemet (levodopa/carbidopa)
co-beneldopa
madopar (levodopa/ benserazide)
how are LDOPA formations taken
tablet formualtions only
pharmacokinetics of LDOPA
mode of action of levodopa
- Once Levodopa has crossed the BBB it must be taken up by dopaminergic cells in the substantia nigra to be converted to dopamine
- As disease progresses and cell degenerated- fewer remaining cells mean levodopa is less reliable- motor fluctuations
advantages of LDOPA
disadvantages of LDOPA
*freezing when drug wearing off*
*requires some cells to be left to produce enzyme for conversion in the SN
Drug-drug interactions LDOPA
- Pyridoxine (vitamin B6) increases peripheral breakdown of L-DOPA
- MAOIs risk hypertensive crisis
- (not MOABIs at normal dose-lose specificity at high dose)
- Many antipsychotic drugs block dopamine receptors and parkinsonism is a side effect (newer, ‘atypical’ antipsychotics less so)
name 2 alternatives to LDOPA
dopamine receptor agonists
Monoamine oxidase B inhibitors
name some Dopamine receptor agonists
uses of dopamine receptor agonists
- Alternative to L-dopa
- Can be first line or add on therapy
Mode of action of dopamine receptor agonists
Mimic dopamine at their receptors
Adverse drug response of dopamine receptor agonists
- Impulse control disorder
- Pathological gambling
- Hypersexuality
- Compulsive shopping
- Desire to increase dose
- Punding- a compulsive need to carry out repetitive behaviour such as sorting materials that you are no longer using
- Sedation
- Hallucinations
- Confusion
- Nausea
- Hypotension
advantages of dopamine receptor agonists
- direct acting
- less dyskinesias/ motor complications
- possible neuroprotection
disadvantages of dopamine receptor agonists
- less efficacy than LDOPA
- impulse control disorders
- more psychiatric symptoms
- expensive
name someMonoamine oxidase B inhibitors
Uses of monoamine oxidase B inhibitors
- Can be used alone to treat IPD
- Prolong action of L-DOPA
- Smooths out motor response
- Maybe neuroprotective
Mode of action of Monoamine oxidase B inhibitors
Inhibits monoamine oxidase B to decrease metabolism of dopamine and therefore increase amount found in synaptic cleft
name 3 COMT inhibitors
Uses of COMT inhibitors
No therapeutic effect alone (can use combination tablets COMT inhibitors and L-DOPA and peripheral dopa decarboxylase inhibitor- Stalevo)
Mode of action of COMT inhibitors
‘L-DOPA sparing effect’- prolonging motor response to L-DOPA to reduce symptoms of wearing off
- Reduces peripheral breakdown of L-DOPA to 3-O-methyldopa
- 3-O-methyldopa competes with L-DOPA active transport into CNS
name some anticholinergics used in parkinsons
minor role in parkinsons- used to treat symptoms e.g. tremor and rigidity
MOA of anticholinergics in parkinsons
- may have an Antagonistic effect to dopamine
advantages of anticholonergics
treat tremor
not acting via dopamine system
disadvantages of anticholinergics
uses of amatadine
parkinsons
- poorly effective
- few side effects
- little effect on tremor
MOA of amantadine
NMDAr inhibition
It is thought to work to control movement problems by increasing the amount of dopamine in certain parts of the body.
ADR amatadine
hallucinations
Surgery for IPD
Myasthenia gravis
- Autoimmune
- Antibodies for AchR on post synaptic membrane
- ‘Fluctuating, fatigable, weakness skeletal muscle’
signs and symptoms of MG
- Extraocular muscles – commonest presentation
- Bulbar involvement – dysphagia, dysphonia, dysarthria
- Limb weakness – proximal symmetric
- Respiratory muscle involvement (myasthenic crisis)
Drugs affecting neuromuscular transmission – exacerbate myasthenia gravis
- Aminoglycosides
- Beta-blockers, CCBs, quinidine, procainamide
- Chloroquine, penicillamine
- Succinylcholine
- Magnesium
- ACE inhibitors
Complications of MG
• Acute exacerbation – Myasthenic crisis
• Overtreatment
– Cholinergic crisis
Therapeutic management of MG
- Acetylcholinesterase inhibitors
- Corticosteroids (treat underlying disease)
- Decrease immune response
- Steroid sparing (treat underlying disease)
- Azathioprine
- IV immunoglobulin
- Acute decline or crisis – 60% will respond after 7-10 days
- Plasmapheresis
- Removes AChR antibodies and short-term improvement
name 2 Acetylcholinesterase inhibitors used to treat MG
pyridostigmine (oral)
neostigmine
pyridostigmine pharmacokinetics
- Onset 30min; peak 60-120min; duration 3-6hr
- Dose interval and timing crucial
- antiacetylcholinesterase side effect – miosis and the SLUDGE syndrome:
- » Salivation,
- » Sweating,
- » Lacrimation
- » Urinary incontinence
- » Diarrhea,
- » GI upset and hypermotility
- » Emesis)
- Neostigmine
-
oral and IV preparations (ITU)
- Quicker action, duration up to 4 hours
- Signidic antimuscarinic side effects
MOA of acetylcholinesterase inhibitors
Mode of action
- Prevents breakdown of ACh in NMJ
- ACh more likely to engage with remaining receptors
- Enhance neuromuscular transmission
- Skeletal and smooth muscle
Adverse drug response of Acetylcholinesterase inhibitors
- Excess dose can cause depolarising block- cholinergic crisis
- Muscarinic side effects
