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Clinical Pharmacology, Therapeutics & Intro to Prescribing > Lecture 24- Neuropharmacology > Flashcards

Lecture 24- Neuropharmacology Flashcards

1
Q

Idiopathic Parkinson’s disease (IPD)

A
  • Neurodegenerative disorder
  • Progressive clinical course
  • Motor symptoms improve with levodopa (symptomatic medication)
  • Non motor symptoms
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2
Q

Pathophysiology of IPD

A
  • 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
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3
Q

Histological hallmarks

A
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4
Q

basal ganglia rev

A
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5
Q

Clinical features of parkinsonism

A
  • Tremor*
  • Rigidity*
  • Bradykinesia**
  • Postural instability ​
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6
Q

Non motor manifestations

A
  • Mood changes
  • Pain
  • Cognitive change
  • Urinary symptoms
  • Sleep disorder
  • Sweating
  • Low Blood Pressure
  • Restless legs
  • Fatigue
  • Hallucinations
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7
Q

Diagnosis of IPD (based on clinical opinion and not on tests)

A
  • Clinical Features
  • Exclude other causes of Parkinsonism
  • Response to Treatment e.g. Levadopa
  • Structural neuro imaging is normal
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8
Q

prognosis

A
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9
Q

Catecholamine synthesis

A
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10
Q

one way to target low dopamine is

A

to prevent its degradation

e.g. COMT or MAO inhibitors

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11
Q

outline neurotransmission starting at synthesis of NT e.g. dopamine

A

AP causes releases into synaptic cleft via action of calcium which causes vesicle docking

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12
Q

treatment of parkinsons disease

A
  • symptomatic e.g. movement disorders and non motor feautres
    • levodopa (LDOPA)
    • dopamine receptor agonists
    • MAOI type B inhibitors
    • COMT inhibitors
    • anticholinergics
    • amatidine
  • Neuroprotection
  • surgery
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13
Q

Why use precursor Levodopa (L-dopa)and not dopamine?

A
  • Dopamine cannot cross the BBB
  • Also causes many peripheral side effects
    • Irregular beart beat
    • Anxiety
    • Headache
    • SoB
    • Nausea
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14
Q

Levodopa

A

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
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15
Q

co-careldopa

A

sinemet (levodopa/carbidopa)

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16
Q

co-beneldopa

A

madopar (levodopa/ benserazide)

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17
Q

how are LDOPA formations taken

A

tablet formualtions only

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18
Q

pharmacokinetics of LDOPA

A
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19
Q

mode of action of levodopa

A
  • 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
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20
Q

advantages of LDOPA

A
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21
Q

disadvantages of LDOPA

A

*freezing when drug wearing off*

*requires some cells to be left to produce enzyme for conversion in the SN

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22
Q

Drug-drug interactions LDOPA

A
  • 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)
23
Q

name 2 alternatives to LDOPA

A

dopamine receptor agonists

Monoamine oxidase B inhibitors

24
Q

name some Dopamine receptor agonists

A
25
Q

uses of dopamine receptor agonists

A
  • Alternative to L-dopa
    • Can be first line or add on therapy
26
Q

Mode of action of dopamine receptor agonists

A

Mimic dopamine at their receptors

27
Q

Adverse drug response of dopamine receptor agonists

A
  • 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
28
Q

advantages of dopamine receptor agonists

A
  • direct acting
  • less dyskinesias/ motor complications
  • possible neuroprotection
29
Q

disadvantages of dopamine receptor agonists

A
  • less efficacy than LDOPA
  • impulse control disorders
  • more psychiatric symptoms
  • expensive
30
Q

name someMonoamine oxidase B inhibitors

A
31
Q

Uses of monoamine oxidase B inhibitors

A
  • Can be used alone to treat IPD
  • Prolong action of L-DOPA
  • Smooths out motor response
  • Maybe neuroprotective
32
Q

Mode of action of Monoamine oxidase B inhibitors

A

Inhibits monoamine oxidase B to decrease metabolism of dopamine and therefore increase amount found in synaptic cleft

33
Q

name 3 COMT inhibitors

A
34
Q

Uses of COMT inhibitors

A

No therapeutic effect alone (can use combination tablets COMT inhibitors and L-DOPA and peripheral dopa decarboxylase inhibitor- Stalevo)

35
Q

Mode of action of COMT inhibitors

A

‘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
36
Q

name some anticholinergics used in parkinsons

A

minor role in parkinsons- used to treat symptoms e.g. tremor and rigidity

37
Q

MOA of anticholinergics in parkinsons

A
  • may have an Antagonistic effect to dopamine
38
Q

advantages of anticholonergics

A

treat tremor

not acting via dopamine system

39
Q

disadvantages of anticholinergics

A
40
Q

uses of amatadine

A

parkinsons

  • poorly effective
  • few side effects
  • little effect on tremor
41
Q

MOA of amantadine

A

NMDAr inhibition

It is thought to work to control movement problems by increasing the amount of dopamine in certain parts of the body.

42
Q

ADR amatadine

A

hallucinations

43
Q
A
44
Q

Surgery for IPD

A
45
Q

Myasthenia gravis

A
  • Autoimmune
  • Antibodies for AchR on post synaptic membrane
  • ‘Fluctuating, fatigable, weakness skeletal muscle’
46
Q

signs and symptoms of MG

A
  • Extraocular muscles – commonest presentation
  • Bulbar involvement – dysphagia, dysphonia, dysarthria
  • Limb weakness – proximal symmetric
  • Respiratory muscle involvement (myasthenic crisis)
47
Q

Drugs affecting neuromuscular transmission – exacerbate myasthenia gravis

A
  • Aminoglycosides
  • Beta-blockers, CCBs, quinidine, procainamide
  • Chloroquine, penicillamine
  • Succinylcholine
  • Magnesium
  • ACE inhibitors
48
Q

Complications of MG

A

• Acute exacerbation – Myasthenic crisis

• Overtreatment
– Cholinergic crisis

49
Q

Therapeutic management of MG

A
  • 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
50
Q

name 2 Acetylcholinesterase inhibitors used to treat MG

A

pyridostigmine (oral)

neostigmine

51
Q

pyridostigmine pharmacokinetics

A
  • 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)
52
Q
  • Neostigmine
A
  • oral and IV preparations (ITU)
    • Quicker action, duration up to 4 hours
    • Signidic antimuscarinic side effects
53
Q

MOA of acetylcholinesterase inhibitors

A

Mode of action

  • Prevents breakdown of ACh in NMJ
  • ACh more likely to engage with remaining receptors
  • Enhance neuromuscular transmission
  • Skeletal and smooth muscle
54
Q

Adverse drug response of Acetylcholinesterase inhibitors

A
  • Excess dose can cause depolarising block- cholinergic crisis
  • Muscarinic side effects

Clinical Pharmacology, Therapeutics & Intro to Prescribing (39 decks)

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