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Exam 1 > Myasthenia Gravis > Flashcards

Myasthenia Gravis Flashcards

1
Q

Myasthenia Gravis is?

A

• autoimmune disease characterised by weakness of the skeletal muscle.

Autoantibodies are made to the nicotinic acetylcholine receptor at the Neuromuscular Junction in skeletal muscle.

Loss of nicotinic acetylcholine receptor at Neuromuscular Junction

Thus transmission through the Neuromuscular Junction is decreased

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2
Q

Myasthenia gravis age and aetiology

A

Risk higher in younger females compared to males

Cause of autoimmune disease is largely unknown

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3
Q

Myasthenia Gravis pathophysiology

A

Loss of nicotinic acetylcholine receptor at neuromuscular junction

Impaired transmission at the NMJ leads to the muscular weakness

Auto-antibodies are made to the muscle nicotinic acetylcholine receptors

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4
Q

Myasthenia signs

Ocular symptoms?

A 
Usually pt present ocular symptoms
- ptosis (drooping eyelids)
- Double vision (diplopia)
• Restricted eye movements
• Worsen when tired
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5
Q

Myasthenia Gravis – Signs/Symptoms

A
  • Lack of facial expression
  • Slurred speech
  • Difficulties chewing
  • Difficulties swallowing (dysphagia)
  • Weakness in arms, legs, neck
  • Shortness of breath - Can be severe – myasthenic crisis
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6
Q

Diagnosing Myasthenia Gravis – Signs/Symptoms

easy?

A

difficult to diagnose as symptoms fluctuate.

In older patients there are similarities to other conditions

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7
Q

Myasthenia Gravis – Tests

A
  • Ice test
  • Blood test for auto-antibodies
    • Neurophysiology
    • Edrophonium test
    • CAT scan to exclude thymoma
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8
Q

Myasthenia Gravis - Ice test

A
  • Simple

* Cooling the muscle improves symptoms

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9
Q

Myasthenia Gravis - Neurophysiology

A

• Electromyogram measures the muscle compound action potential in
response to repeated stimulation

compound action potential in muscle decreases despite repeated stimulation

decrease in the size of the muscle response

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10
Q

Myasthenia Gravis - Edrophonium

A

• Edrophonium is a short-acting cholinesterase inhibitor

• Injection of edrophonium causes increase in muscle strength (ptosis is
reversed)

• Rarely used due to side effects

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11
Q

Myasthenia Gravis long-term condition?

A

yes

most pt can live normal lives w/o significant impacts of life expectancy

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12
Q

Myasthenia Gravis Severity

A

fluctuates

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13
Q

Myasthenia Gravis progression

A

Usually progresses to affect other muscles
• 80% of patients show progression from ocular MG
• Progression can be rapid (weeks) or slow (years)

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14
Q

Myasthenia Gravis - life-threatening?

A

YES
• Myasthenic crisis
• Affects 20% of patients at some point in their lives
• Acute respiratory failure - diaphragm is skeletal muscle so no transmission through NMJ at diaphragm, pt cant breathe so Acute respiratory failure. Medical emergency
• Requires mechanical ventilation

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15
Q

why Myasthenia Gravis can cause acute respiratory failure

A

diaphragm is skeletal muscle so no transmission through NMJ at diaphragm, pt cant breathe so Acute respiratory failure. Medical emergency

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16
Q

Myasthenia Gravis – Treatment

A

• Acetylcholinesterase inhibitors (anticholinesterases)

  • Eg. Pyridostigmine
  • Symptomatic relief

• Immunosuppressive therapy

  • Oral steroids
  • Other immunosuppressants Eg. Azathioprine, ciclosporine

• Intravenous immunoglobulin or plasma exchange
- For rapidly deteriorating MG or myasthenic crisis

• Thymectomy - removal of the thymus gland

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17
Q

NMJ events EDIT

A
  1. Action potential propagation in motor neuron
  2. Ca2+ passes Voltage gated Calcium channel
  3. Nicotinic acetylcholine receptors release ACh from vesicles
  4. acetylcholinesterase cleaves ACh
  5. Na+ exits, K+ enters synaptic cleft via Na/K pump.
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18
Q

Management of MG

A
  • Avoid disease triggers known to exacerbate the disease
  • Symptomatic treatment to produce - minimal symptoms + minimal drug side effects. acetylcholinesterase inhibitors which increase amount of ACh at neuromuscular junction
  • Immunosuppressant drugs which treat underlying immune dysfunction.
  • Immunomodulatory treatments eg. plasma exchange, use of immunoglobulins, surgery
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19
Q

MG triggers

A

anything that exacerbates muscle weakness

  • Infection - ensure annual flu vaccination taken
  • Stress or trauma
  • Thyroid dysfunction
  • Withdrawal of acetylcholinesterase inhibitors
  • Rapid introduction or increase of corticosteroids
  • Anaemia
  • Electrolyte imbalances due to other drugs.
  • Medicines
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20
Q

exacerbates muscle weakness

A
  • Infection - ensure annual flu vaccination taken
  • Stress or trauma
  • Thyroid dysfunction
  • Withdrawal of acetylcholinesterase inhibitors
  • Rapid introduction or increase of corticosteroids
  • Anaemia
  • Electrolyte imbalances due to other drugs.
  • Medicines
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21
Q

Meds to avoid unavoidable then?

A

pt should be titrated slowly and monitor disease and deterioration if they do take these medicines

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22
Q

Meds to avoid that Increase muscle weakness

A
  • Magnesium - causing hypermagnesaemia
  • Benzodiazepines
  • Beta-blockers
  • Diuretics (secondary to electrolyte disturbances)
  • Verapamil
  • statins
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23
Q

Meds to avoid that Interferes with neuromuscular transmission

A
  • Phenytoin, carbamazepine
  • Aminoglycosides, colistimethate, clindamycin, fluoroquinolone, macrolides, telithromycin
  • Antimuscarinic agents (unless s/e Tx?)
  • Procainamide and lidocaine
  • Lithium, chlorpromazine
  • Hydroxychloroquine
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24
Q

MG – symptomatic treatment

A

• Oral acetylcholinesterase inhibitor
- Pyridostigmine (neostigmine used less due to shorter duration of action)

  • Provide a variable improvement in strength then increase to get control of pt symptom w/o adverse effects
  • Dosing – starting 15mg QDS with food
  • Assess cholinergic s/e
  • Typical maintenance 60mg four to six times a day
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25
Q

Oral acetylcholinesterase inhibitor too high dose

A

too high dose = can suffer with choline crisis due to excessive ACh inhibitors

26
Q

MG – symptomatic treatment adverse effects

A

dose dependent and predictable (based on nicotinic and muscarinic effects):
• Nicotinic effects – muscle and abdominal cramps
• Muscarinic – gut hypermobility (cramps and diarrhoea), increased sweat/salivations/lacrimation, hypotension, bradycardia, miosis, urinary incontinence, increased bronchial secretions and tachypnoea (rapid breathing)

27
Q

Cholinergic crisis

A

excessive acetylcholinesterase inhibitor treatment, causes weakness and is hard to distinguish from worsening MG.

28
Q

Management of side effects of treatment

A
  • Taking with food can mitigate GI s/e
  • Co-prescribing oral anti-cholinergic drugs that have little or no effect on nicotinic receptors thus do not produce muscle weakness
  • • Glycopyrrolate
  • • Propantheline

• Diarrhoea - loperamide

29
Q

MG Pharmaceutical care Considerations

A
  • Drugs exacerbating MG
  • Monitoring
  • Ability to swallow or use oral medication
  • Treatment step-up
30
Q

Modulators of Acetylcholine

Enhancers of Acetylcholine Action

A

Nicotinic agonists

Acetylcholine esterase inhibitors

31
Q

Nicotinic agonists therapeutic

A

Not used therapeutically as v.low activity

Introduction of a methyl group into acetylcholine at the alpha position to the N results in a selective nicotinic agonist

32
Q

Acetylcholine esterase inhibitors - therapeutic option

A

Therapeutic option is reversible.

enhances muscle strength e.g. myasthenia gravis
increase no. of ACh circulating in neuromuscular junction

Can also be used to reverse muscle relaxants

Inhibition of acetylcholine esterase enhances action of acetylcholine

Normally, acetylcholine is degraded rapidly in vivo - acts as a control mechanism

33
Q

Acetylcholine esterase inhibitors - non-therapeutic option

A

Irreversible molecules made – poisons e.g. sarin, organophosphate insecticides

34
Q

Acetylcholine esterase

A

ACh held in place in enzyme by important binding interactions through H bonding with Tyrosine, ionic bonding with another Aspartic acid, presence of hydrophobic pockets that can accommodate methyl substituent on N

35
Q

Hydrolysis of acetylcholine in acetylcholinesterase

A
  1. ACh undergoes nucleophilic attack from the Serine moiety
  2. from tetrahedral intermediate, histidine aids movement of a proton from Serine to ACh to provide good leaving group within ACh
  3. e- then fed back in from oxygen and ester of ACh is broken. ACh destroyed. enzyme becomes inactivated as Serine became acylated
  4. enzyme must be regenerated to transport another molecule of ACh
36
Q

Regeneration of enzyme

A

occurs through water acting as nucleophile

  1. H2O nucleophile attacks carbonyl on acylated serine
  2. histidine aids movement of proton from water molecule onto the serine residue to make that the best leaving group
  3. feeding in of e- leads to breaking of ester thus regenerating serine nucleophile
  4. serine nucleophile is regenerated so now can degrade another ACh molecule
37
Q

Carbamates (ureathanes)

A
  • Contain a leaving group which is equal in efficiency of dissociation to the acetyl group in acetylcholine
  • Leaving group should produce a residual group bound to serine which is less susceptible to hydrolysis
  • Contain a positively charge to fix the molecule into correct orientation in the active site
38
Q

Carbamates why good?

A

charged nitrogen mimics the charged nitrogen in acetylcholine ensuring excellent binding in the receptor

carbamate makes enzyme difficult to regenerate

phenol group = excellent leaving group, needed to make mechanism occur

Pyrrolidine Nitrogen can be charged at physiological pH to allow strong docking into enzyme

39
Q

Carbamates

A

generate carbamated enzyme instead of acylated enzyme to make reversible inhibitor
regeneration step to give free serine is much slower but is done

40
Q

Carbamates

Derivatives of Physostigmine

A

phenol group for additional enzyme binding interactions

carbamate for enzyme inactivation

charged/chargeable nitrogen for enzyme binding

41
Q

Carbamates

Derivatives of Physostigmine examples

A

miotine: simplified version of physostigmine. SEs as it enters brain

neostigmine, pyridostigmine - permanent +ve charge thus cannot cross BBB so reduced CNS effects

42
Q

Irreversible AChE inhibitors why?

therapeutic?

A

Not therapeutic

Death occurs through asphyxia as muscles cannot be controlled due to too high levels of ACh

rather than ester being formed at the enzyme, phosphate ester formed which is more resistant to hydrolysis, leaving groups promote first part of reaction mechanism at the enzyme. Stability of phosphate ester = enzyme not regenerated in hours. hours is considered irreversible as rate of enzyme acylated in seconds, carbamated in minutes,

43
Q

Irreversible AChE inhibitors examples

A

Organophosphates
- Form a covalent bond – irreversible inhibitors

Include:

  • organophosphate insecticides
  • nerve agents

Sarin
VX
Chlorophos

44
Q

Inhibition of AChE causes

A

causes an increase in ACh at the synaptic cleft prolonging its activity

45
Q

Examples of AChE for myasthenia gravis

A

Neostigmine, pyridostigmine

46
Q

Examples of AChE for insecticide (headlice)

A

Malathion

47
Q

Examples of AChE for Alzheimer’s disease

A

Donepezil

48
Q

2 types of cholinesterase

A

Acetylcholinesterase (AChE)

Butyrylcholinesterase (BuChE)

49
Q

Acetylcholinesterase (AChE)

A

– Can be membrane bound (synaptic cleft) or in soluble form
(pre-synaptic terminal; cerebrospinal fluid)

– Found at ACh synapses

– Specific for ACh

50
Q

Butyrylcholinesterase (BuChE)

A

– Widespread distribution – plasma, liver, skin

– Broader substrate specificity

– Genetic variant for BuChE activity (reduced activity)

51
Q

Drugs that inhibit Cholinesterase

3 main groups:

A

– Short-acting eg. Edrophonium

– Medium duration eg neostigmine, pyridostigmine, donepezil

– Irreversible eg malathion, Dyflos, Sarin, VX, “Novichok”

52
Q

Acetylcholine

A

action of acetylcholine in the synaptic cleft is terminated by acetylcholinesterase

degraded by AChE into

choline and acetate

53
Q

AChE inhibitors at NMJ

A

Increase in twitch tension as more ACh, increases size of contraction

54
Q

Effects of cholinesterase inhibitors

A

Cholinesterase inhibitors are parasympathomimetic

Parasympathetic synapses (post-ganglionic) eg.
Physostigmine, organophosphates
55
Q

Parasympathetic

if ACh inhibited

A

rest and digest

all increased if ACh inhibited:

decreased heart rate/bradycardia

decrease cardiac output

vasodilation of blood vessels/arterioles via release of NO, decreases blood pressure

increase in SM contraction except vascular SM so

  • increase in peristaltic activity
  • bladder contraction
  • bronchiole constriction

GIT increases motility (sphincter relacation)

Pupil contraction

Glands secretion

56
Q

CVD impact of AChE inhibitors

A

decreased heart rate/bradycardia

decrease cardiac output

vasodilation of blood vessels/arterioles via release of NO, decreases blood pressure

57
Q

CVD impact of AChE inhibitors

A

decreased heart rate/bradycardia

decrease cardiac output

vasodilation of blood vessels/arterioles via release of NO, decreases blood pressure

58
Q

eye impact of AChE inhibitors

A

Pupil constriction

constriction of ciliary muscle (accommodation)
→ ↓ intraocular pressure

59
Q

Glands impact of AChE inhibitors

A

– ↑ secretion (salivation, lacrimation, bronchial secretion, digestive enzymes, sweating)
• NB Sweat glands – cholinergic synapse, sympathetic nervous system (the odd one out…)

60
Q

Acetylcholinesterase inhibitors larger doses

A

• Larger doses can cause depolarization block of autonomic ganglia and the NMJ due to excessive ACh

  • They also have central effects if they can cross the BBB including:
  • Improved cognition (therapeutic)
  • Convulsions, unconsciousness, respiratory failure (toxicity)
61
Q

Pyridostigmine is an example of which class of drugs?

A

Acetylcholinesterase inhibitors

62
Q

Which of the following is a side effect of acetylcholinesterase inhibitors?

A) Diarrhoea
B) Dry eye
C) Dry mouth
D) Dry skin
E) Tachycardia
A

AChE inhibitor increases Ach. Stimulates parasympathetic NS. More Ach increases gut movement. Leads to diarrhoea.

Exam 1 (11 decks)

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