Myasthenia Gravis

Question 1

What’s Myasthenia Gravis?

Answer 1

1- Myasthenia gravis is an autoimmune disease characterised by weakness of the skeletal muscle.

2- Autoantibodies are made to the nicotinic acetylcholine receptor in skeletal muscle. Transmission through the NMJ is decreased

Autoimmune disease characterised by weakness of muscle because the autoantibodies are made to the nicotinic acetylcholine receptor in the skeletal muscle and that means transmission through the neuromuscular junction is decreased.

Question 2

Epidemiology of MG

Answer 2

Incidence 5.3/1million
Prevalence 77.7/1million
Mortality 0.2-0.9/1million

Uk prevalence estimates at 15/100,000 in 2012

The number are underestimated due to lack of diagnosis in older patients.

Prevalence is a measure of the frequency of a disease or health condition in a population at a particular point in time (and is different to incidence, which is a measure of the number of newly diagnosed cases within a particular time period).

Question 3

Aetiology of MG

Answer 3

Causes and risk factors of the disease
Age
Different distribution between males and females biomodal
Females-peaks between 20-30 years
Makes-peaks between 60-80 years old
Risk higher in younger females compared to males

Causes of the autoimmune disease is largely unknown
Pathophysiology- loss of nAChRs at the NMJ. Loss of nicotinic acetylcholine receptors.

Why do we make autoantibodies to our own proteins and why that specific nicotinic receptor?

Autoantibodies are produced when the immune system mistakenly targets and attacks the body’s own proteins. In the case of myasthenia gravis, a specific autoimmune disorder, autoantibodies are generated against the nicotinic acetylcholine receptor (nAChR) located at the neuromuscular junction. The exact reasons for this autoimmune response are not completely understood, but there are a few possible explanations:

1. Molecular Mimicry: It is possible that the immune system recognizes a foreign substance, such as a viral or bacterial protein, that shares structural similarities with the nAChR. The immune response initiated against the foreign substance may also target the nAChR due to the molecular mimicry, leading to the production of autoantibodies.
2. Genetic Factors: Certain genetic variations can predispose individuals to develop autoimmune disorders like myasthenia gravis. These genetic factors can affect the regulation of the immune system or the recognition of self-proteins, including the nAChR, leading to an autoimmune response.
3. Dysfunction of Regulatory T cells: Regulatory T cells (Tregs) play a crucial role in maintaining immune tolerance and preventing the attack on self-proteins. Dysfunction or deficiency of Tregs may result in the breakdown of immune tolerance, allowing the immune system to produce autoantibodies against the nAChR.
4. Other Factors: Environmental factors, such as infections or exposure to certain medications, may trigger or contribute to the development of autoantibodies against the nAChR in susceptible individuals. However, the specific triggers and mechanisms involved in myasthenia gravis are still being investigated.

It is important to note that myasthenia gravis is a complex autoimmune disorder, and the production of autoantibodies against the nAChR is just one aspect of the disease. Further research is needed to fully understand the underlying causes and triggers of myasthenia gravis.

Question 4

What are the signs and symptoms do MG?

Answer 4

Ocular symptoms:
Ptosis is drooping eyelids.
Diplopia, double vision.
Restricted eye movements, worsen when tired.

1-lack of facial expression
2- Slurred speech
3- Difficulties chewing
4- Difficulties swallowing dysphagia
5- Weakness in arms, legs, neck
6- Shortness of breath, can be severe-Myasthenic crisis.

Can be difficult to diagnosis since symptoms fluctuate. In older patients there are similarities to other condition like that of stroke.

Question 5

What tests are done to diagnose MG?

Answer 5

1- Ice tests:
Simple and cooling the muscles improves symptoms.

2- Blood tests for auto-antibodies

3- Neurophysiology:
Electromyogram measures the muscle compound action potential in response to repeated stimulation
See a decrease in the size of the muscle response.

4- Edrophonium test:
Edrophonium is a short acting cholinesterase inhibitor.
Injection of edrophonium causes increase in muscle strength (ptosis is reversed)
Rarely used due to side effects

(Incidence not known of s/e

Chest pain or discomfort
dizziness
fainting
fast, slow, or irregular heartbeat
increased frequency of urination
increased sweating
lightheadedness, dizziness, or fainting
loss of bladder control
muscle twitches that are visible under the skin
seizures
slurred speech
trouble breathing
trouble speaking
unusual tiredness)

5- CAT scan to exclude thymoma.

Question 6

Natural history of MG

Answer 6

Long term condition but doesn’t impact life expectancy.
Severity fluctuates
Starts with ocular symptoms
Ocular myasthenia gravis
Progresses to affect other muscles happens in 80% of patients
Progression can be rapid or slow (weeks-years)

Life threatening:

Myasthenic crisis
Affects 20% of patients, can lead to acute respiratory failure that will require mechanical ventilation.

Question 7

What is the treatment of MG?

Answer 7

1- Acetylcholinesterase inhibitors (anti-cholinesterases):
Pyridostigmine gives symptomatic relief

2- Immunosuppressive therapy
Oral steroids and other immunosuppressants eg Azathioprine, ciclosporine.

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

4- Thymectomy

Question 8

Pathophysiology of MG

Answer 8

Myasthenia Gravis is an autoimmune disease, characterised by muscle weakness and it is a disease of the neuromuscular junction NMJ.

Impaired transmission at the NMJ leads to the muscular weakness.

Autoantibodies are made against the muscle nicotinic acetylcholine receptors that are specifically in the NMJ. If we make those autoantibodies against the nicotinic receptor which are critical in transmitting information across the synapse the muscle transmission is going to be affected.

Question 9

How does transmission occur at the NMJ?

Answer 9

At the neuromuscular junction (NMJ), transmission occurs through a process known as synaptic transmission.

1. Action Potential: When a nerve impulse reaches the end of a motor neuron, it triggers the opening of voltage-gated calcium channels. This influx of calcium ions causes synaptic vesicles containing neurotransmitters to fuse with the presynaptic membrane.
2. Neurotransmitter Release: The fusion of synaptic vesicles with the presynaptic membrane leads to the release of neurotransmitters, such as acetylcholine (ACh), into the synaptic cleft.
3. Binding to Receptors: ACh diffuses across the synaptic cleft and binds to the specific receptors located on the postsynaptic membrane of the muscle fiber. These receptors are called nicotinic acetylcholine receptors (nAChRs).
4. Generation of Muscle Action Potential: The binding of ACh to nAChRs triggers the opening of ligand gated ion channels, allowing sodium ions (Na+) to enter the muscle fiber and potassium ions (K+) to exit. This change in ion concentrations generates a muscle action potential.
5. Contraction: The muscle action potential propagates along the muscle fiber, causing the release of calcium ions from the sarcoplasmic reticulum. The calcium ions bind to troponin, leading to the exposure of myosin-binding sites on actin filaments. This allows myosin heads to bind to actin, initiating muscle contraction.
6. Termination: Acetylcholinesterase, an enzyme located in the synaptic cleft, breaks down the remaining ACh molecules, preventing continuous stimulation of the muscle fiber. The reuptake of choline by the presynaptic membrane allows for the synthesis of new ACh molecules.

If we lose nicotinic receptors this will impair transmission and this happens in MG autoantibodies cause a loss of receptors and cause loss of transmission.

Question 10

What are the most affected muscles?

Answer 10

Use dependent muscles
The most affected muscles are those in most use, giving classic symptoms such as ptosis and lack of facial expression.

Question 11

Pharmacology of MG treatment?

Answer 11

Anti-cholinesterase inhibitors work by inhibiting the action of acetylcholinesterase on the NMJ this stops the breakdown of acetylcholine and more of it will be available in the synapses, this increases activity and improves muscle contraction.

Question 12

Cholinesterase inhibitors-pharmacology
Slide-2 diagram

Answer 12

The diagram you provided illustrates some of the targets for drug action at the cholinergic synapse. Here is a breakdown of the components and their associated drug targets:

1. Acetyl CoA (AcCoA): AcCoA is involved in the synthesis of acetylcholine (ACh) and serves as a precursor for ACh production.
2. Choline: Choline is transported into the presynaptic neuron by a choline carrier. Drugs that target the choline carrier, such as hemicholinium, can inhibit choline uptake and thereby decrease ACh synthesis.
3. Vesamicol: Vesamicol is a drug that inhibits the vesicular acetylcholine transporter (VAT). By blocking the transport of ACh into synaptic vesicles, vesamicol disrupts ACh release during synaptic transmission.
4. CAT (Choline Acetyltransferase): CAT is the enzyme responsible for the synthesis of ACh from choline and AcCoA. Modulating the activity of CAT can affect ACh production.
5. Presynaptic Nicotinic ACh Receptor: The presynaptic nicotinic ACh receptor is located on the presynaptic membrane of the neuron. It is a target for drugs that modulate the release of ACh, such as presynaptic toxins like botulinum toxin.
6. ACh Carrier: The ACh carrier is responsible for the reuptake of ACh from the synaptic cleft into the presynaptic neuron. Drugs that target the ACh carrier, such as certain antidepressants, can inhibit ACh reuptake and increase the concentration of ACh in the synapse.
7. ACh: Acetylcholine is the primary neurotransmitter at the cholinergic synapse. It binds to and activates postsynaptic receptors, triggering a response in the postsynaptic neuron or target tissue.
8. Empty Vesicle: Empty vesicles represent the depletion of ACh in synaptic vesicles following neurotransmitter release.
9. Choline Carrier: The choline carrier is responsible for the reuptake of choline from the synaptic cleft into the presynaptic neuron for ACh synthesis.
10. Exocytosis: Exocytosis is the process by which synaptic vesicles release their contents, including ACh, into the synaptic cleft.
11. Presynaptic Toxins (e.g., botulinum toxin): Presynaptic toxins like botulinum toxin can inhibit ACh release by disrupting the machinery involved in exocytosis.
12. Hemicholinium: Hemicholinium is a drug that inhibits the choline carrier, reducing choline uptake and subsequently decreasing ACh synthesis.
13. ACh Leak: ACh leak refers to the spontaneous release of ACh from the presynaptic neuron, independent of action potentials.
14. Non-depolarizing Blocking Agents (e.g., tubocurarine): Non-depolarizing blocking agents, such as tubocurarine, block the postsynaptic nicotinic ACh receptors, preventing ACh from binding and inhibiting muscle contraction.
15. Depolarizing Blocking Agents (e.g., suxamethonium): Depolarizing blocking agents, like suxamethonium, initially activate the postsynaptic nicotinic ACh receptors, causing muscle depolarization. However, they then desensitize the receptors, resulting in muscle paralysis.
16. AChE (Acetylcholinesterase): Acetylcholinesterase is the enzyme responsible for the breakdown of ACh in the synaptic cleft. Anticholinesterase drugs, such as neostigmine

Question 13

Cholinesterase inhibitors

Answer 13

The action of acetylcholine in the synaptic cleft is terminated by acetylcholinesterase AChE

Inhibition of acetylcholinesterase causes an increase in ACh at the synaptic cleft prolonging it is activity.

Several therapeutic agents act by inhibiting cholinesterase;

1-Neostigmine, pyridostigmine-MG
2-Malathion insecticide headlice
3-Donepezil alzaheimers disease

Question 14

How many types of cholinesterases are there? And state their role?

Answer 14

There are 2 types of cholinesterase:
1-Acetylcholinesterase AChE
2-Butyrylcholinesterase BuChE

1-AChE: can be membrane bound (synaptic cleft) or in soluble form (presynaptic terminal; cerebrospinal fluid)
Found at ACh synapses
Specific for ACh

2-BuChE
Widespread distribution-plasma, liver, skin
Broader substrate specificity
Genetic variant for BuChE activity-(reduced activity)

Cholinesterase inhibitors inhibit each of these in different proportions.

Question 15

What drugs inhibit cholinesterase?

Answer 15

1-Edrophonium (short acting)

2-Neostigmine, pyridostigmine, donepezil. (Medium duration)

3-Malathion, Dyflos, sarin, VX, Novichok (Irreversible) referred to as organophosphate

Question 16

Where do cholinesterase act,

Answer 16

If they are inhibiting acetylcholine, they will act on any synapses that has acetylcholine.

1- Somatic efferent system: acetylcholine is released at the NMJ to cause contraction of skeletal muscle. So acetylcholinesterase inhibitors are going to affect skeletal muscle contraction.

2- Sympathetic system: acetylcholine is released at the sympathetic system at sweat glands and also acetylcholine is released in the autonomic ganglia

3- Parasympathetic system: post-ganglionic neurone releases acetylcholine acting on muscarinic receptor at target organs like salivary glands, heart and smooth muscles. All those organs will be affected by acetylcholinesterase inhibitors.

Question 17

What are the effects of cholinesterase inhibitors?

Answer 17

slide 7-
Neostigmine and pyridostigmine work best at the neuromuscular junction.

We release acetylcholine it acts at the post synaptic receptor to cause muscle contraction, we get rid of it in the synaptic cleft by breaking it down via acetylcholinesterase, if we block the action of acetylcholinesterase this will augment the action of acetylcholine and this in turn will increase the intensity of muscle contraction this is referred to as increase in twitch tension. If there is too much acetylcholine this leads to depolarisation block.

Slide-8
Actions at parasympathetic nervous system, we have post ganglionic synapses Wight he target organ. The irreversible organophosphates irreversible cholinesterase inhibitors have a selectively for working at at PNS.

Cholinesterase inhibitors are parasympathomimetic, mimic what the PNS does.

Question 18

What is the effect of AChE on the role of PNS?

Answer 18

PNS= rest and digest
Decrease in
heart rate,
blood pressure dilation in the arteriole
Constriction of the bronchi
Increase in the gut motility sphincter relaxation.
Bladder contraction, emptying of bladder.
Eyes constriction of the pupil
PNS causes Glandular secretion-
exocrine

If we increases the acetylcholine by blocking acetylcholinesterase from breaking down the acetylcholine in the NMJ or synaptic cleft we augment the action of ACh

Question 19

What are the effects of cholinesterase inhibitors?

Answer 19

1-Cardiovascular system normally the PNS slowed the heart down Bradycardia. Cholinesterase is also going to slow down the heart and it will decrease cardiac output and vasodilation because acetylcholine causes a release of Nitrogen oxide and NO causes vasodilation of the arterioles. Decrease in cardiac output and increase in vasodilation this’ll cause a decrease in blood pressure.

2-Smooth muscle
Acetylcholine acting at muscarinic receptors causes contraction of smooth muscle, we have smooth muscle in the gut we contract the smooth muscle and this will increase the peristaltic activity so increase gut motility.

Bladder contraction emptying of bladder

Constriction of bronchioles, when resting we don’t need airways to be dilated so when resting we constrict airways as a result of cholinesterase inhibitors we get bronchoconstrictions. This is because cholinesterase inhibitors are mimicking the PNS.

Eyes: constriction of pupil and constriction of ciliary muscle so we will not be able to focus on things because acetylcholine causes contraction of ciliary muscles. Overall this will cause intraocular pressure (glaucoma).

Glands: PNS increases secretion like (salivation, lacrimation, bronchial secretion, digestive enzymes, sweating)
Overall the effect of cholinesterase inhibitors is going to increase glandular secretion.

Question 20

What happens in an overdose of cholinesterase inhibitors?

Answer 20

Larger doses can cause depolarisation block of autonomic ganglia and the NMJ due to excessive ACh.

They also have central effects if they can cross the blood brain barrier. Effect include:
Improved cognition that is why it is used in Alzheimer’s disease.
Convulsions
Unconsciousness
Respiratory failure
Toxicity

Question 21

Clinical:
Acetylcholinesterase inhibitors

Answer 21

1-Describe key pharmaceutical care issues of the treatment of MG

2-Describe therapeutics of the acetylcholinesterase inhibitors used in the symptomatic treatment of MG

Question 22

Management of MG?

Answer 22

MG is a chronic but treatable disease and many patients can achieve sustained remission and full functioning capacity.

Management:
1-avoid disease triggers.
2-symptomatic treatment (cholinesterase inhibitors) to produce minimal symptoms + minimal drug side effects
3-immunosuppressant drugs
4-immunomodulatory treatments include plasma exchange and use of IgG and potentially surgery

Question 23

What exacerbates MG?

Answer 23

Anything that exacerbates muscle weakness:

1-Infection patients with generalised or pulmonary effects of MG should have the annual flu vaccination and pneumococcal vaccine to reduce their risk of getting these infections.
Equally patients on drugs that modulate immune response means patients are less likely to mount an appropriate response against an infection.
Pharmacist must ensure that patient with infection is receiving correct drug and it’s effects are monitored to make sure it is effective.

2-Stress or trauma

3-Thyroid dysfunction, pharmacist has role in monitoring patient thyroid function, this related to affect of drugs on patient thyroid function

4-Withdrawal of acetylcholinesterase inhibitors

5-Rapid introduction or increase of corticosteroids

6-Anaemia

7-Electrolyte imbalance, monitoring for signs of electrolyte imbalances due to other medications.

8-Medicine pharmacist should always check for co-prescribed medications for their risks of deteriorating patients
MG.

Pharmacist play a key role both in secondary and primary care setting in ensuring patient has reduced risk of these triggers.

Question 24

What medication affect symptoms of MG?

Answer 24

There are medications that interfere with neuromuscular transmission and medications that increase muscle weakness.

1-Interfere with neuromuscular transmission:
Phenytoin
Carbamazepine
Amino-glycosides
Colistimethate
Clindamycin
Fluoroquinolonr
Macrolides
Telithromycin
Anti-muscarinic agents
Procainamide and lidocaine
Lithium
Chlorpromazine
Hydroxychloroquine

2-Increase muscular weakness
Mg causes hypermagnesaemia
Benzodiazepines
Beta-blockers
Diuretics (secondary to electrolytes disturbances)
Verapamil
Statins
Patient should always avoid these medications but it is not possible all the time and if treatment is indicated patient must be titrated very cautiously and carefully monitored for deterioration of their MG.
As a pharmacist you should always evaluate all prescriptions for patients with MG for their risk of deteriorating MG symptoms.

Question 25

Symptomatic treatment of MG

Answer 25

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

Provide a variable improvement in muscle strength, this varies between patients some patient could have major improvement some patients not so much. Patient may see improvements in some of their symptoms but not all symptoms.

Dosing- starts 15mg QDS with food
-assess cholinergic side effects tablets come as 60mg tablet can be halved or quartered to make up the required dose. Increase treatment to get control of patient symptoms but not to cause excessive adverse effects.
-typical maintenance 60mg four times to six times a day, doses typically taken with food, this reduces the GI side effects from pyridostigmine.

Adverse effects- dose dependent and predictable (nicotinic and muscarinic effects)
-nicotinic effects: muscle and abdominal cramps

-muscarinic: gut hypermobility (cramps, diarrhoea), increases sweat, salivation, lacrimation, hypotension, bradycardia, miosis(pupil constriction), urinary incontinence, Increases bronchial secretion and tachyponea.

Question 26

What happens in an overdose of pyridostigmine?

Answer 26

In an overdose of pyridostigmine, patients will suffer from a cholinergic crisis is the result of excessive acetylcholinesterase inhibitors treatment.
-This causes weakness and is hard to distinguish from worsening MG
-With the described doses this is rarely, if ever. Ensuring patient has the right dose is key in reducing patient risk of adverse effects and cholinergic crisis.

Role of pharmacist is management of potential side effects.
Reducing the likelihood of s/e or having treatment for s/e if they occur.

1- taking with food mitigate GI s/e

2- co-prescribing oral anti-cholinergic drugs ( that have little or no effect on nicotinic receptors (I.e. don’t produce muscle weakness) like Glycopyrrolate, propantheline, these can reduce soem side effects of acetylcholinesterase inhibitors.

Diarrhoea can be controlled using loperamide.

Anti-cholinergic drugs:

Anticholinergic medications (shorthand: “anticholinergics”) are drugs that block and inhibit the activity of the neurotransmitter acetylcholine (ACh) at both central and peripheral nervous system synapses.[1] In doing so, these drugs inhibit the actions of the parasympathetic nervous system (the “rest and digest”

When given with acetylcholinesterase inhibitors it helps in counteracting the side effects of these drugs and help relieve side effects symptoms. And they little or no effect on nicotinic receptors so they won’t cause muscle weakness.

Question 27

Pharmaceutical care of MG

Answer 27

We need to consider co-prescribed drugs in summary as having the potential to worsen patients condition.
We need to review these drugs to determine to see if any of them effect MG and if they are specifically indicated or an alternative medication can be used instead. It is important to monitor patient closely for deterioration of their MG.

Monitor for signs and symptoms associated with drug use.
Deteriorating of MG symptoms is important and how they can be managed with step up treatment or increasing dosing.

Patient with generalised MG or myasthenic crisis may not have the ability to swallow or use oral medication. Ensure other formulations available for patient.

Treatment step-up incase of exacerbation of their symptoms.

Question 28

Medchem
Modulators of acetylcholine

Question 29

How can modulators of acetylcholine be used to improve muscle contraction for patients?

Answer 29

By enhancing the activity of acetylcholine at nicotinic receptors. To enhance effect of acetylcholine, an obvious way of doing that is to make acetylcholine like molecules, agonists that will work preferentially at nicotinic receptors.

Molecules like the one shown in slide 1 which has substituent alpha to the nitrogen, can be selected for nicotinic receptors. However they can’t be used therapeutically because they show very low activity.

Instead acetylcholinesterase inhibitors are used to increase the concentration of circulating acetylcholine at the neuromuscular junctions thus altering the natural control mechanism to breakdown acetylcholine. If the inhibition is reversible we have THERAPEUTIC molecules, irreversible inhibitors like sarin and insecticides.

The therapeutic molecules have a role in the treatment of myasthenia gravis, but they also have a role in treatment of glaucoma and are being developed for the treatment of Alzheimer.

Question 30

Acetylcholine esterase inhibitors

Answer 30

•Therapeutic option-enhances muscle strength eg myasthenia gravis.

•Can also be used to reverse muscle relaxants.

•Inhibition of acetylcholine esterase potentiates the action of acetylcholine

•In normal situation acetylcholine is degraded rapidly in vivo- acts as a control mechanism.

•Reversible-Therapeutic

•Irreversible-poison eg sarin, organophosphate insecticide.

Acetylcholine esterase inhibitors therapeutic reversible molecules have a role in the treatment of MG; a disease whose primary feature is muscle weakness, particularly the muscles of the face, which leads to problems with the eye and swallowing. They also have shown to have a role in the treatment of glaucoma and Alzheimer’s disease. In addition to these roles, they also can be used to reverse the effects of muscle relaxants.

Question 31

How does the enzyme acetylcholine esterase work?

Answer 31

It is a serine protease and consists of a catalytic triad made of aspartic acid, histidine and serine.

•Acetylcholine is held in place in the active site through an ionic interaction between the nitrogen and another aspartic acid.

•There is a hydrogen bonding interaction between the ether like oxygen and tyrosine and hydrophobic pockets for the methyl substituents. These binding interactions set up the carbonyl perfectly for the reaction with the enzyme.