S12) Neuropharmacology Flashcards by shreya Arun

Identify four clinical features of Parkinsonism

Tremor
Rigidity
Bradykinesia
Postural instability

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

What are the non-motor manifestations of Parkinson’s disease?

Mood changes
Pain
Cognitive change
Urinary symptoms
Sleep disorder
Sweating

How well did you know this?

Not at all

Perfectly

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 well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

what is bradykinesia

movements get slower as movement continues

How well did you know this?

Not at all

Perfectly

Describe the pathological features of IPD

Neurodegeneration
Lewy bodies synucleinopathy
Loss of pigment
Reduced dopamine

How well did you know this?

Not at all

Perfectly

what percentage of dopaminergic neurones are lost in the basal ganglia before any motor signs are visible

50% lost

How well did you know this?

Not at all

Perfectly

Describe three ways in which the basal ganglia circuitry is affected in IPD

How well did you know this?

Not at all

Perfectly

Identify six different drug classes used to treat IPD

Levodopa (L-DOPA)
Dopamine receptor agonists
MAOI type B inhibitors
COMT inhibitors
Anticholinergics
Amantidine

How well did you know this?

Not at all

Perfectly

catecholamine synthesis

How well did you know this?

Not at all

Perfectly

dopamine degradation

How well did you know this?

Not at all

Perfectly

Why is L-DOPA used to treat IPD instead of Dopamine?

How well did you know this?

Not at all

Perfectly

How is Levodopa administered?

Oral administration

→ not soluble but can be dispersed

→ dispersable Madopar

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

What is the half life of L-DOPA?

T_1/2= 2 hours

How well did you know this?

Not at all

Perfectly

What are the advantages of L-DOPA?

Highly efficacious
Low side effects e.g. nausea, vomiting, hypotension, tachycardia, psychosis

How well did you know this?

Not at all

Perfectly

What are the disadvantages of L-DOPA?

Loss of efficacy (only effective in presence of dopaminergic neurones)
Needs enzyme conversion
Involuntary movements
Motor complications

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

what are some examples of peripheral dopa decarboxylase inhibitor

→ Co-careldopa (sinemet

→ Co-beneldopa (madopar)

How well did you know this?

Not at all

Perfectly

what are some advantages of taking levodopa

→ highly efficacious

→ few side effects:

How well did you know this?

Not at all

Perfectly

what are some disadvantages of taking levodopa

How well did you know this?

Not at all

Perfectly

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: **s**alivation, **s**weating, **l**acrimation, **u**rinary incontinence, **d**iarrhea, **G**I upset and hypermotility, **e**mesis

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