Myasthenia Gravis Flashcards
Myasthenia Gravis is?
• 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
Myasthenia gravis age and aetiology
Risk higher in younger females compared to males
Cause of autoimmune disease is largely unknown
Myasthenia Gravis pathophysiology
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
Myasthenia signs
Ocular symptoms?
Usually pt present ocular symptoms - ptosis (drooping eyelids) - Double vision (diplopia) • Restricted eye movements • Worsen when tired
Myasthenia Gravis – Signs/Symptoms
- Lack of facial expression
- Slurred speech
- Difficulties chewing
- Difficulties swallowing (dysphagia)
- Weakness in arms, legs, neck
- Shortness of breath - Can be severe – myasthenic crisis
Diagnosing Myasthenia Gravis – Signs/Symptoms
easy?
difficult to diagnose as symptoms fluctuate.
In older patients there are similarities to other conditions
Myasthenia Gravis – Tests
- Ice test
- Blood test for auto-antibodies
• Neurophysiology
• Edrophonium test
• CAT scan to exclude thymoma
Myasthenia Gravis - Ice test
- Simple
* Cooling the muscle improves symptoms
Myasthenia Gravis - Neurophysiology
• 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
Myasthenia Gravis - Edrophonium
• Edrophonium is a short-acting cholinesterase inhibitor
• Injection of edrophonium causes increase in muscle strength (ptosis is
reversed)
• Rarely used due to side effects
Myasthenia Gravis long-term condition?
yes
most pt can live normal lives w/o significant impacts of life expectancy
Myasthenia Gravis Severity
fluctuates
Myasthenia Gravis progression
Usually progresses to affect other muscles
• 80% of patients show progression from ocular MG
• Progression can be rapid (weeks) or slow (years)
Myasthenia Gravis - life-threatening?
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
why Myasthenia Gravis can cause acute respiratory failure
diaphragm is skeletal muscle so no transmission through NMJ at diaphragm, pt cant breathe so Acute respiratory failure. Medical emergency
Myasthenia Gravis – Treatment
• 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
NMJ events EDIT
- Action potential propagation in motor neuron
- Ca2+ passes Voltage gated Calcium channel
- Nicotinic acetylcholine receptors release ACh from vesicles
- acetylcholinesterase cleaves ACh
- Na+ exits, K+ enters synaptic cleft via Na/K pump.
Management of MG
- 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
MG triggers
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
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
Meds to avoid unavoidable then?
pt should be titrated slowly and monitor disease and deterioration if they do take these medicines
Meds to avoid that Increase muscle weakness
- Magnesium - causing hypermagnesaemia
- Benzodiazepines
- Beta-blockers
- Diuretics (secondary to electrolyte disturbances)
- Verapamil
- statins
Meds to avoid that Interferes with neuromuscular transmission
- Phenytoin, carbamazepine
- Aminoglycosides, colistimethate, clindamycin, fluoroquinolone, macrolides, telithromycin
- Antimuscarinic agents (unless s/e Tx?)
- Procainamide and lidocaine
- Lithium, chlorpromazine
- Hydroxychloroquine
MG – symptomatic treatment
• 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
Oral acetylcholinesterase inhibitor too high dose
too high dose = can suffer with choline crisis due to excessive ACh inhibitors
MG – symptomatic treatment adverse effects
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)
Cholinergic crisis
excessive acetylcholinesterase inhibitor treatment, causes weakness and is hard to distinguish from worsening MG.
Management of side effects of treatment
- 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
MG Pharmaceutical care Considerations
- Drugs exacerbating MG
- Monitoring
- Ability to swallow or use oral medication
- Treatment step-up
Modulators of Acetylcholine
Enhancers of Acetylcholine Action
Nicotinic agonists
Acetylcholine esterase inhibitors
Nicotinic agonists therapeutic
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
Acetylcholine esterase inhibitors - therapeutic option
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
Acetylcholine esterase inhibitors - non-therapeutic option
Irreversible molecules made – poisons e.g. sarin, organophosphate insecticides
Acetylcholine esterase
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
Hydrolysis of acetylcholine in acetylcholinesterase
- ACh undergoes nucleophilic attack from the Serine moiety
- from tetrahedral intermediate, histidine aids movement of a proton from Serine to ACh to provide good leaving group within ACh
- e- then fed back in from oxygen and ester of ACh is broken. ACh destroyed. enzyme becomes inactivated as Serine became acylated
- enzyme must be regenerated to transport another molecule of ACh
Regeneration of enzyme
occurs through water acting as nucleophile
- H2O nucleophile attacks carbonyl on acylated serine
- histidine aids movement of proton from water molecule onto the serine residue to make that the best leaving group
- feeding in of e- leads to breaking of ester thus regenerating serine nucleophile
- serine nucleophile is regenerated so now can degrade another ACh molecule
Carbamates (ureathanes)
- 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
Carbamates why good?
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
Carbamates
generate carbamated enzyme instead of acylated enzyme to make reversible inhibitor
regeneration step to give free serine is much slower but is done
Carbamates
Derivatives of Physostigmine
phenol group for additional enzyme binding interactions
carbamate for enzyme inactivation
charged/chargeable nitrogen for enzyme binding
Carbamates
Derivatives of Physostigmine examples
miotine: simplified version of physostigmine. SEs as it enters brain
neostigmine, pyridostigmine - permanent +ve charge thus cannot cross BBB so reduced CNS effects
Irreversible AChE inhibitors why?
therapeutic?
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,
Irreversible AChE inhibitors examples
Organophosphates
- Form a covalent bond – irreversible inhibitors
Include:
- organophosphate insecticides
- nerve agents
Sarin
VX
Chlorophos
Inhibition of AChE causes
causes an increase in ACh at the synaptic cleft prolonging its activity
Examples of AChE for myasthenia gravis
Neostigmine, pyridostigmine
Examples of AChE for insecticide (headlice)
Malathion
Examples of AChE for Alzheimer’s disease
Donepezil
2 types of cholinesterase
Acetylcholinesterase (AChE)
Butyrylcholinesterase (BuChE)
Acetylcholinesterase (AChE)
– Can be membrane bound (synaptic cleft) or in soluble form
(pre-synaptic terminal; cerebrospinal fluid)
– Found at ACh synapses
– Specific for ACh
Butyrylcholinesterase (BuChE)
– Widespread distribution – plasma, liver, skin
– Broader substrate specificity
– Genetic variant for BuChE activity (reduced activity)
Drugs that inhibit Cholinesterase
3 main groups:
– Short-acting eg. Edrophonium
– Medium duration eg neostigmine, pyridostigmine, donepezil
– Irreversible eg malathion, Dyflos, Sarin, VX, “Novichok”
Acetylcholine
action of acetylcholine in the synaptic cleft is terminated by acetylcholinesterase
degraded by AChE into
choline and acetate
AChE inhibitors at NMJ
Increase in twitch tension as more ACh, increases size of contraction
Effects of cholinesterase inhibitors
Cholinesterase inhibitors are parasympathomimetic
Parasympathetic synapses (post-ganglionic) eg. Physostigmine, organophosphates
Parasympathetic
if ACh inhibited
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
CVD impact of AChE inhibitors
decreased heart rate/bradycardia
decrease cardiac output
vasodilation of blood vessels/arterioles via release of NO, decreases blood pressure
CVD impact of AChE inhibitors
decreased heart rate/bradycardia
decrease cardiac output
vasodilation of blood vessels/arterioles via release of NO, decreases blood pressure
eye impact of AChE inhibitors
Pupil constriction
constriction of ciliary muscle (accommodation)
→ ↓ intraocular pressure
Glands impact of AChE inhibitors
– ↑ secretion (salivation, lacrimation, bronchial secretion, digestive enzymes, sweating)
• NB Sweat glands – cholinergic synapse, sympathetic nervous system (the odd one out…)
Acetylcholinesterase inhibitors larger doses
• 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)
Pyridostigmine is an example of which class of drugs?
Acetylcholinesterase inhibitors
Which of the following is a side effect of acetylcholinesterase inhibitors?
A) Diarrhoea B) Dry eye C) Dry mouth D) Dry skin E) Tachycardia
AChE inhibitor increases Ach. Stimulates parasympathetic NS. More Ach increases gut movement. Leads to diarrhoea.
