S12) Neuropharmacology Flashcards
Identify four clinical features of Parkinsonism
- Tremor
- Rigidity
- Bradykinesia
- Postural instability
what are some added features of Parkinsonism
→ sometimes they can’t stop their movements so keep moving
→ sometimes can’t start their own movements without a push
→ lead pipe rigidity (resistance in movement)
→ cog wheeling → moving joints slowly
→ shuffle gait
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: Bradykinesia
- Exclude other causes of Parkinsonism
- Response to treatment: 70-80% levadopa,
- Normal structural neuro-imaging
what is bradykinesia
movements get slower as movement continues
Describe the pathological features of IPD
- Neurodegeneration
- Lewy bodies synucleinopathy
- Loss of pigment
- Reduced dopamine
what percentage of dopaminergic neurones are lost in the basal ganglia before any motor signs are visible
50% lost
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
catecholamine synthesis
dopamine degradation
Why is L-DOPA used to treat IPD instead of Dopamine?
How is Levodopa administered?
Oral administration
→ not soluble but can be dispersed
→ dispersable Madopar
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
→ 9% converted into dopamine in peripheral tissues by dopa decarboxylase
⇒ Forms monoamine oxidase & DOPA decarboxylase
Despite the patient being on medication why will the medication be less useful over time
→ over time the patient is still losing dopaminergic neurones
→ There wont be enough neurones to convert the dopamine
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
what is levodopa always given in conjunction with
→ peripheral dopa decarboxylase inhibitor
→ you want the dopamine to work centrally not peripherally otherwise you will get unwanted side effects
→ this means a reduced dose is required and more levodopa reaching brain
what are some examples of peripheral dopa decarboxylase inhibitor
→ Co-careldopa (sinemet
→ Co-beneldopa (madopar)
what are some advantages of taking levodopa
→ highly efficacious
→ few side effects:
what are some disadvantages of taking levodopa
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
→ they have no therapeutic effect by themselves always have to use levodopa and dopa decarboxylase inhibitor)
Provide an example of a COMT inhibitor
Entacapone (doesn’t cross BBB)
Opicapone (doesn’t cross BBB)
Dopamine receptor agonists
→ you can start on these before giving ladopa
Non Ergot: Ropinirole, Pramipexole
Patch: if they have swallowing difficulties (Rotigotine)
Subcutaneous: Apomorphine
when do you use dopamine receptor agonist
→ de novo therapy
→ apomorphine (for patients with severe motor fluctuations) subcutaneous:
→ bolus
→ continuous infusion
advantages for dopamine receptor agonist
→ no peripheral effect
disadvantages for dopamine receptor agonist
dopamine receptor agonists side effects
→ sedation
→ hallucinations
→ confusion
→ nausea
→ hypotension
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
→ autoimmune, immunoglobulin blocks the Act receptors so Ach can’t get in
Describe the presentation of Myasthenia gravis
- Extraocular muscles – commonest presentation (ptosis)
- Bulbar involvement – dysphagia, dysphonia, dysarthria
- Limb weakness – proximal symmetric
what does movement look like in myasthenia graves
→ muscle movements become more slow, eg: eye is open and it slowly closes as there is a depletion in the amount of Ach
→ once the eye is rested then there is more Ach and the eye can be kept open again
cycle repeats
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 (respiratory failure, swallowing problems)
- Overtreatment – cholinergic crisis (muscle paralysis)
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) → quicker action, duration up to 4 hours
pyridostigmine
onset 30 mins, peak 60-120 mins, duration 3-6 hours
→ must make sure to give 40 mins before eating so that patients can actually swallow
What are the antimuscarinic side effects of acetylcholinesterase inhibitors?
- Miosis
- SSLUDGE syndrome: salivation, sweating, lacrimation, urinary incontinence, diarrhea, GI upset and hypermotility, emesis
what are some impulse control disorders
→ pathological gambling
→ hyper sexuality
→ compulsive shopping
→ desire to increase dose
→ pending (constantly rearranging things)
Monoamine oxidase B inhibitors use
→ can be used alone
→ prolong action of levodopa
→ smooths out motor response
how do monoamine oxidase B inhibitors work?
→ monoamine oxidase B metabolises dopamine and is mainly found in the dopamine regions in the brain
→ these inhibitors will enhance dopamine in the brain
what are some examples of monoamine oxidase B inhibitors
→ Selegiline
→ Rasagaline
→ Safinamide
when is surgery used
→ stereotactically
→ deep brain stimulation: insert electrode into brain
→ controlled trials
