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Structure and function of skeletal muscles
Therefore, they will contract when we make a conscious decision to move
Skeletal muscles are under voluntary control
The fibres leading to muscles are myelinated for fast conduction of action
potentials
Remember: NMDA and AMPA in the spinal cord will open their ion
channels in response to glutamate for FAST depolarisation
The motor neurones in the spinal cord use glutamatergic synpases
Needs to reach from the brain down to all the muscles
They need to be fast, because they tend to be the longest cells in the body
They need to conduct information from the brain to the muscle quickly forproper control
Schwann cells in the periphery are responsible for wrapping their
membranes around the axon of the nerve to cover it in lipids
Keeps the axon insulated against the leakage of ions, allows for faster
connections
Dense in ion channels, causes the influx of ions at these points to
continue the conduction of the action potential
There are regular breaks in the myelin wraps though, these are call the
nodes of Ranvier
Multiple Sclerosis (MS) is one of them
Incurable
If these neurones are to become demyelinated, the control of skeletal
muscles can be lost
Again, myelin is used to increase conduction speeds within neurones
AnteriorMotor nerves leave the spinal cord from the ventral roots
This is called a motor unit
Having a greater 'nerves to muscle fiber' ratio leads to better control of
the muscle
i.e. if one nerve controls every 3 muscle fibres, then you can have fine
control, because you can turn on muscle fibres in multiples of 3, allowing
for a wide range of forces generated by the overall muscle
But if one nerve controls 200 fibres, it's more difficult to have fine control
because you can only activate muscle fibres in multiples of 200, so it's
hard to specifically control how much force is generated
Each nerve will activate a few muscle fibres at the same time
Skeletal muscles will use ACh (acetylcholine) as the transmitter at the
neuromuscular junction (NMJ)
Neuromuscular Junction (NMJ)
This is where the nerve meets the muscle fibre
Allows the muscle to contract evenly, because the depolarisation spreads
from the middle out
If it were to be on the end, then one end will contract faster than the
other end, leading to poor co-ordination between muscles
Tends to be located at the middle of fibres
Action potential reaches the nerve terminal, and that opens the voltage
gated calcium channel
Calcium will allow the vesicle to undergo exocytosis
The process at the NMJ is:
Cholinergic control at the NMJ
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They are cut by the botulinum A toxin, which prevents exocytosis
and causes paralysis
SNARE proteins are used to anchor the vesicle onto the membrane for
exocytosis
i.e. these receptors will bind strongly to nicotine and ACh
Once ACh is released into the cleft, it can travel to the motor endplate
and bind to Nicotinic Cholinergic receptors
Called the excitatory post synaptic potential (EPSP)
Must reach the potential threshold as well to trigger a muscle-wide
depolarisation and contraction
This leads to opening of the channel, which causes sodium influx to
depolarise the muscle
Depolarisation leads to opening of the voltage gated calcium channels of
the sarcoplasmic reticulum
This causes an increase in calcium, which leads to contraction
Meanwhile, the ACh in the cleft is broken down into choline
Choline is rapidly taken back up into the neurone
It is metabolised into ACh by CAT using Acetyl CoA
The ACh is repackaged into vesicles via a fast and specific transporter
located on the vesicles
Cholinergic receptors
NMJ (as seen above)
Adrenal gland
Ganglia of both the sympathetic and parasympathetic systems
Causes initial increase in blood pressure and heart rate,
followed by a decrease in blood pressure and heart rate
Therefore, it's not a good idea to have a non-selective nACh
agent as it will cause a whole lot of side effects
High dose nicotine leads to initial sympathetic activation followed
by parasympathetic activation
Nicotinic ACh receptors (nAChR)
Muscarinic ACh receptors
ACh is quite commonly used around the body
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Mostly at the organ of the parasympathetic system
Some glands under sympathetic control
We will be focusing on nAChR as they are used in the NMJ
5 subunits per receptor
Each subunit contributes their helix to the ion pore in the middle
Allows for specific targeting of the receptors (but not 100%selectivity, so there is some cross-reactivity at high concentrations)
Muscle uses 2 alpha-1 subunits, 1 beta-1 subunit, 1 gamma subunit
and 1 eta subunit
Different types of receptors (muscle, CNS and ganglionic) uses different
mixes of subunits
There are 11 different types of subunits
Both binding sites must have ACh attached to open the channel
In muscle the two alpha subunits are important as they have the binding sites
for ACh
Short distance to diffuse across
The binding of ACh is very fast
ACh esterase (AChE) will quickly break down ACh into choline and acetate
It comes off very fast
A lot of sodium can pass into the muscle in that time to cause
depolarisation
Even if it stays on for 1ms it has an action
Blockers at the NMJ
There are some therapeutic uses of blocking actions at the NMJ
Reflexes aren't shut down, they will spasm if cut
This can cause major damage during surgery
One of them is to cause paralysis during surgery to prevent the patient from
moving around
The diaphragm is an important muscle in breathing
It is under voluntary control
Therefore, blocking actions at the NMJ causes paralysis of the muscle,
which stops the patient from breathing
Blockers must be used with artificial ventilation and careful supervision
But there is a huge problem with blocking actions at the NMJ
ACh esterase inhibitors
Autoimmune reaction, antibodies made against the nACh receptorsin the muscle endplate
Prevents their activation by ACh, which causes muscle weakness
If we block AChE, then there will be more ACh in the cleft to trigger
more nAChR to increase muscle strength
Treatment of Myasthenia Gravis
Organophosphates will covalently bond to the AChE to inactivate
them
Leads to too much ACh being in the cleft
Remember: the diaphragm is under voluntary control,
organophosphates will lead to paralysis so you stop breathing
The ACh receptors in the motor endplate will stop reacting to ACh,
because the ion channels are kept open (see below for a phase I
block)
We don't cause too much activation. If you happen to cause
Why doesn't paralysis occur in the treatment of myasthenia gravis?
War agent/pesticides
The AChE can be inhibited for three reasons
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too much activation, then that causes the paralysis
Antidote to non-depolarising block agents (see below)
Non-depolarising block
Causes paralysis by preventing ACh from having an effect at the ion
channel
BUT pain and other senses are not affected, if people aren't knocked outcompletely, then they can hear and feel themselves being cut apart
These agents are antagonists at the receptor
Very low (if any) bioavailability
All of them have a quarternary ammonium, therefore, they are pretty
much positively charged
Curare-based compounds were found to be non-depolarising blockers
Called the safety-factor of transmission which is natural protection
against neuromuscular blocking agents
Slow onset because 70-80% of the receptors need to be blocked before
paralysis occurs
We can try to reverse this by using cyclodextrins (rings of sugars) to
try and 'suck out' the drug of the receptor to stop their action
Slow recovery because they bind tightly to the receptor and stay there
These relaxants all have a slow onset and recovery
Eyes, then the face, then the limbs etc.
But importantly, the respiratory muscles are the last to be paralysed,
which also gives us some protection from death if a blocker was
administered
Once the agent is metabolised, the order is the same but in reverse
(respiratory muscles first, eyes last)
The blocker will cause paralysis to certain parts of the body first
Not selective enoughCauses hypotension
Older agents can actually block ganglionic nACh receptors
Because this is competitive antagonism of the nAChR, we can give the person a
AChE to increase ACh to outcompete the blocker to restore normal function
Depolarising block
Causes initial contraction, then paralysis
Initial contraction comes from the activity before the phase I block sets in
These agents are agonists at the receptor
The ion channels are kept open by the agent
The increase in voltage (depolarisation) is important, not the
absolute value
Therefore, depolarisation isn't possible, because it's already
depolarised (kept at 0mV)
So ACh release has no effect on the endplate (already depolarised)
Phase I
Tachyphylaxis/sensitisation
The ion channels naturally close due to a safety mechanism, causing
hyperpolarisation again (cell voltage drops back to -70mV)
They won't open again in response to ACh for a while now
Phase II
There are two phases which are important to the action of these agents
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Two ACh molecules linked together
Not as quickly compared to ACh, half-life of 4-6 minutes compared
to a second at most
Liked by surgeons due this short period of action
Give a large initial bolus dose (quick paralysis) followed by IV
infusion to maintain for the duration of the surgery
Metabolised by a cholinesterase (but not AChE)
Causes both Phase I then Phase II block
Suxamethonium (Sux) is a clinically used agent
AChE just allows more agonists to be present
Actually makes the paralysis WORSE!
These agents CANNOT be reversed by AchE
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ACh and SAR
ACh is quite a simple molecule (shown top)
Susceptible to hydrolysis (shown bottom)
Simple ester on the left
Always ionised
Same goes for choline as well
Requires an active transporter to get it across the membrane
Quaternary nitrogen on the right
AChE inhibitors
May be reversible or irreversible
But both are competitive. i.e. will bind at the active site instead of ACh
Edrophonium chloride is a reversible AChE inhibitor
Stable in water (Stays for awhile in the cleft)
This is because the positive charge on the carbon attached to
the serine means it's easier to remove the residues of the
agent
In ACh, this positive charge is quite high, which is why it's
kicked off so quickly
In the blocker, the positive charge on the carbon is reduced
due to resonance with the nitrogen atom
Stable in the enzyme (the enzyme-inhibitor complex takes a few
minutes to clear (compared to a few milliseconds with ACh)
Carbamate esters are resistant to hydrolysis
This class of inhibitors all have a carbamate ester instead of a simple ester
Medchem
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No positive quarternary nitrogen though
Contains a carbamate
Allows access to the Canal of Schlemm for optic drainage to counter
glaucoma, which is where the pressure inside the eye is too great
Under muscarinic ACh control
Is also studied for its effects to improve cognition in Alzheimers disease
Physostigmine is able to work in the eye to contract the pupil
Irreversible AChE inhibitors
Organophosphates
These are phosphate esters
If you go back above, it is mentioned that the positive charge on the
carbon attached to serine determines how quickly it is kicked off the
enzyme
The irreversible inhibitors undergo a process of aging, where it loses its
ester groups while it's attached
This further reduces the positive charge on the phosphate, meaning it
can't be kicked off, so the active form of the enzyme can't be regenerated
The reason why they are so effective is due to the strength of bonding of the
residues to the serine
Non-depolarising agents
Notice it has two quaternary nitrogen groups, which are always charged
Remember: charge not needed to bind to AChE though
Also notice how ACh also has a quaternary nitrogen group, which is
important in binding to the receptor
The distance between the two nitrogens is about 1.4nm, or about a 10-12
carbon chain
The spacer between them is not as important
This distance is very important
Tubocurarine is a non-depolarising agent
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They use a steroid as a spacer between the nitrogens
Why a steroid? The plant just makes them like that. If it works, it works.
Rapid onset and medium-long acting
If either the liver or kidney are damaged, then clearance is reduced
Why? Because having at least one ester intact (coloured as red)
means it's still active. Therefore, since it has an active metabolite,
both metabolism and excretion are important factors in clearance
Renally eliminated, but metabolised in the liver
Pancuronium and Vecuronium are aminosteroids
Very good, doesn't rely on the patient's organ function for
elimination
Plus it has a shorter half-life
Non-enzymatic Hoffman elimination
Instead, it is base catalysed (we still got some OH- in water remember?)
Note: I don't know if we have to know the mechanism, but it's quite
simple
These esters may be cleaved but the more important thing is the
alpha carbon next to it
There is an alpha carbon located next to the esters
And the positive charge from the nearby nitrogen helps too
The alpha carbon has a surprisingly acidic hydrogen due to the positive
charge on the carbonyl carbon
Then, this reaction occurs (called the Hoffman elimination reaction)
Atracurium is quite interesting due to its elimination
Depolarising agents
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Same as above, but these are connected by a flexible chain
The most commonly used one is suxamethonium (AKA Succinylcholine)
If a person lacks this esterase, then they are paralysed for longer
(apnea)
Rapidly cleaved by a cholinesterase (but not AChE, which is why it lingers
around for longer)
Short half-life (desirable)
Notice it has two simple esters
Estrogen receptor modulators
Prevents side effects (e.g. tender breasts, abnormal bleeding etc)
Antagonist at the breast and uterus
Prevents the breakdown of bone
Agonist at osteoblasts and osteoclasts
Raloxifene (pictured below) is an
Vitamin D
Important as a hormone in its final form (calcitriol or 1,25-
dihydroxycholecalciferol)
The conversion of 7-Dehydrocholesterol to cholecalciferol by UV light
falling on the skin
Dietary intake of cholecalciferol
Obtained from UV irradiated mushrooms, actually works pretty
good
Dietary intake of ergrocalciferol
May be obtained from:
Converted from cholecalciferol to calcidiol (or 25-hydroxycholecalciferol) in the
liver
Converted to its final calcitriol form in the kidneys
Calbindin is used in the lumen of the GI tract to bind calcium to make it
easier to absorb into the body
Calcitriol will bind to the DNA after it binds to a intracellular receptor (it's a
steroid) to cause transcription, especially for calcium binding protein (or
calbindin, seriously who names these things? Give him/her a medal for making
calcium-related things so obviously easy!)
Since it causes increased calcium absorption, it increases the chance of
calcified kidney stones from forming (ouch)
Major adverse reaction:
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Bisphosphonates
Two phosphate groups
R1 is almost always OH (clodronate is the only exception, uses Cl)
R2 can be modified to change its activity
Have a very simple SAR:
Just the middle carbon is an oxygen
Normally in the bone, we have pyrophosphate, which looks very similar to
bisphosphonates
But this is offset by the fact that it accumulates nicely in the bone
WARNING: this chelation means it must NOT be taken with
magnesium, iron or calcium containing products. Otherwise they'd
chelate and prevent either being absorbed
This is REALLY important because the people taking
bisphosphonates may be taking a calcium supplement as well.
Tell them to take bisphosphonates at least 30 minutes before the
calcium supplement
This is due to the phosphate groups and the OH group will chelate to
calcium
Overall, the absorption of the bisphosphonates is low due to its polarity and thehalf-life in the plasma is short
Least potent
Only has a simple carbon sidechain for R2
First generation
There are three generations to consider:
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More potent (x100)
Has a simple nitrogen-containing sidechain for R2
Second generation
Even more potent (x10,000)
Has a heterocyclic ring containing sidechain for R2
Third generation
Except for clodronate (uses Cl, is first generation)
Notice how all three generations have OH for R1
But both rely on the fact that osteoclasts break down bone, which
releases the bisphosphonate for the osteoclast to absorb
Metabolised into compounds which compete with ATP to cause
osteoclasts to apoptose
First generation:
Inhibits farnesyl diphosphate synthase (FPPS) in the HMG-CoA
reductase pathway (AKA melvonate pathway)
Causes changes in the cells' GTPases which affects normal function
(e.g. prevents the ruffled border formation with the bone) and cell
survival and generation (make less cells, they survive shorter
periods of time)
Second generation:
Debate about its effectiveness in osteoporosis
Not thought to be effective because it just doesn't build up in bone
like bisphosphonates
There's another class of drugs which inhibits the HMG-CoA reductase
pathway, and that's the statins
Their mechanisms of actions slightly differ
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Note
The first part is very similar to the lecture given in Oncology
The notes for this lecture assumes you understand everything from that lecture
This lecture may reinforce prior knowledge or add extra details
The lecture has also missed out on a LOT of NSAID related side effects.
These have been filled in
We will focus mainly on the drugs and COX pathways
Revision of the terms (some are from previous years)
From the nerve to the spine
From the spine to the thalamus of the brain
From the thalamus to the sensory cortex
Usually consists of several neurones
Pain pathways
Somatic pain- Easy to describe and locate as it's mapped to a certain
part of the brain
Visceral pain- Hard to describe and locate as it's not as accurately
mapped in the brain. Usually deep tissue injuries or organs
Caused by the activation of receptors in response to a stimulus
Nociceptive pain
Caused by the spontaneous activation of nerves without a response to a
stimulus. Tends to be caused by damage to nerves (compression,
inflammation, ischemic damage and metabolic injury)
Neuropathic pain
Occurs from a specific identifiable incident (i.e. you knew it happened),
which goes away within days to weeks. Caused due to nociceptive pain
Acute pain
Not easy to figure out where the pain is coming from. May keep going
indefinitely. Can be nociceptive or neuropathic
Chronic pain
Small, myelinated fibres for fast conduction. Used for physical and
thermal pain to cause sharp pain
A-delta-fibres
Unmyelinated fibres for slow, chronic conduction. Causes burning pain
C-fibres
Important safety reflexes carried out at the spinal level before central
involvement
This is because speed is key, we don't have time to think and give orders
to avoid further injury (e.g. touching a flame, and wincing backwards)
Sensory information feeds into the spine (as usual)
But interneurones in the spine will feed back information into motor
nerves and trigger them to trigger the reflex
Spinal/local reflexes
Increased pain due to a painful stimulus. Could be due to sensitisation at
the nerve endings and increased central sensitisation
Hyperalgesia
Non-painful stimuli are felt as pain. e.g. pressure being felt on the skin
could be interpreted as pain if the area is sunburnt
Allodynia
Inflammation and pain
Pain (again) and inflammation
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Calor- Heat produced at the site of action due to vasodilation and
increased blood flow. Increased cellular metabolism also increases the
local heat
Rubor- Redness at the site due to vasodilation and increased blood flow
Tumor- Swelling due to vasodilation and leakier capillaries.
Dolor- Pain, which is caused by the release of mediators and pressure on
the nerve ending due to swelling
Loss of function
First off, inflammation causes 5 things at the site of injury:
Acute- vasodilation and leakier capillaries to allow immune cells to move
into the region
Subacute- Infiltration of cells into the region
Chronic- Repair or fibrosis occurs in the region
There are three phases of inflammation as well
As you may or may not know, NSAIDs are highly recommended for
inflammatory pain, and this is due to COX inhibition
Common to most cells in the body
Therefore, most cells will be producing COX-1 products at a basal
level
So if a drug blocks COX-1, then you can expect to see gastric
side effects
One of these things is PGI2 which is used to reduce gastric acid
secretion
Important for vasodilation in the kidneys to maintain them
If PGE2 is reduced, then renal damage can precipitate
Therefore, if anyone has renal insufficiencies (or are diabetic
because they have fragile kidneys), they need to avoid COXinhibitors
Remember: PGE2 is also important for gastric protection
Another prostaglandin being produced is PGE2
Causes vasoconstriction and platelet aggregation
Normally kept balanced by PGI2 (which reduced aggregation)
PGI2 production is reduced if COX-2 is blocked, which leads to
increased clotting
Lastly, the difference between COX-1 and 2 is the production of
thromboxane A2
COX-1
Induced during inflammation, which makes it a drug target
Proinflammatory prostaglandins such as PGE2 will not only causesensitisation at the nerve ending, it can also trigger pain by itself
Another role of PGI2 is to prevent platelet aggregation
Blocking COX-2 will reduce PGI2, which increases the chances
of platelet aggregation and clot formation
However, it also is responsible for producing PGI2 as well
COX-2
Is like COX-1
But found in the brain to produce prostaglandins there
Probably where paracetamol works (diclofenac and ibuprofen
would be too polar to get here)
COX-3
But there arethree COX isoforms in the body
The gene which codes for COX-2 has a region for glucocorticoids to bind
to
If glucocorticoids bind here, it prevents the transcription of COX-2 to
reduce inflammation
Glucocorticoids play a role here
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COX-1 doesn't have a region for glucocorticoids, so they don't affect
COX-1
IL-1 is a very important cytokine which is also used to increase body
temperature (i.e. has pyrogenic effects)
The thermoregulatory centre is there
IL-1 causes activation of cells to produce PGE2 in the hypothalamus of the
brain to increase body temperature
Umm I thought he said NSAIDs won't get into the brain oh well.NSAIDs (and paracetamol) will block the production of PGE2
NSAIDs have an antipyretic effect
Side effects of NSAIDS
COX-1 activity is present in the body, and it is important for normal tissue
homeostatic
Therefore if we block it, then we're bound to cause some effects
COX-1 is responsible for the production of PGI2 and PGE2, both will act to
reduce gastric acid secretion to prevent gastric/duodenal damage
Gastric effects
COX-1 is responsible for the production PGE2, which is important for renal
vasodilation and renal health
Renal effects
See above for thromboxane A2 is produced by COX-1 and it's responsible
for increased platelet aggregation, while PGI2 produced by both COX-1
and COX-2 inhibits aggregation. Selective inhibition of COX-2 cause
Cardiovascular events
COX inhibition leads to increased levels of leucotrienes, which are
implicated in bronchospasm and bronchoconstriction
Therefore, for asthmatics, they should be recommended paracetamol,
and if they are given NSAIDs, they should be told to look out forsymptoms and discontinue NSAIDs if they occur
NSAID induced asthma
Can lead to swelling of the body and rashes
Systemic shock can be fatal
Hypersensitivity reactions
Drugs
Very important for its anti-coagulatory activity at low doses, as
platelets cannot regenerate COX-1, so they can't producethromboxane A2 (which prevents platelet aggregation
Irreversible binding to COX-1
Unknown action
Also has analgesic action at high doses
Damage caused by COX-1 inhibition is bad enough
But further damage is caused by direct irritation of the lining if
aspirin is allowed to come into contact with the stomach lining
GI effects are severe
Aspirin
Non-selective COX inhibitor
Has the lowest amount of side effects, so it's our first line NSAID
Ibuprofen
But it's activity is 1:5 selection for COX-2
Non-selective COX inhibitor
Higher risk for GI symptoms
Diclofenac
Paracetamol
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Due to chemical definition, it doesn't have an easily ionisable acid
Not an NSAID
Good for analgesia and antipyretic effects
Be wary of a overdose of paracetamol, causes severe liver damage
Considered to be very well tolerated
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Quick intro
DMARD stands for Disease modifying anti-rheumatic drugs
NSAIDs
Glucocorticoids
Analgesics
Because rheumatoid arthritis is a chronic inflammatory disease
They are given as a part of a combined treatment with:
Typically has immunosuppressant functions to reduce damage
Are not analgesics or anti-inflammatory (which is why we have the other
drugs as well)
The role of DMARDs is to prevent damage to the joint
Weeks to months
Need to have symptomatic relief while they get to work
They take a long time to have their actions
Methotrexate
Seems to be a very popular DMARD
3-4 weeks instead of several months
Fast onset of action
Shown to be safe in pregnancy
It's cheap and it's been around for awhile now
Monitor LFTs
Hepatotoxicity
Monitor blood counts
Myelotoxicity/myelosuppression
Skin reactions
Has adverse effects
Remember: lymphocytes rely on de novo synthesis of purines,
which is why this pathway is so important to them
Inhibits dihydrofolate reductase (DHFR), which inhibits the conversion of
dihydrofolate (DHF) to the useful tetrahydrofolate (THF) which is used for
pyrimidine and purine depletion
Also causes indirect inhibition of thymidylate synthase indirectly by
increasing DHF levels
This leads to reduction of proliferation of T cells
Mechanism of action is well known
Dosed orally once a week
I think it affects purine synthesis more at these lower doses, since the
depletion of thymine (a pyrimidine) causes apoptosis...
Doses are lower compared to the doses used in chemo
Also causes extracellular adenosine release, which somehow reduces
inflammation. The mechanism is unknown
Teratogenic, use another DMARD
Leflunomide
Prodrug which targets pyrimidine synthesis
This also means lymphocytes are restricted from dividing due to a lack of
nucleotides (similar situation compared to methotrexate)
Similar efficacy to methotrexate
DMARDs
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Hepatotoxicity and myelosuppression
This is also teratogenic, use another DMARD
Has similar adverse effects as well:
Hypertension
But it can also cause:
Gold salts
Considered to be a late stage drug, consider other drugs before gold saltsLong time to action, needs 3-4 months for action
Dermatitis
Flu-like symptoms
Diarrhoea
Hypersensitivity reactions
Nephritis (and kidney damage)
Common (33% of patients see them) and severe side effects:
But it causes immunosuppression
Mechanism of action is unknown (yay!)
Sulfasalazine
We have met this drug during inflammatory bowel conditions
5-aminosalicylic acid (5-ASA)
Sulfapyridine
But if it reaches the large intestine (either due to enterohepatic
recirculation or just as it moves through the GI tract) the bacteria there
will cleave it into:
Absorbed in the small intestine as whole sulfasalazine
5-ASA is a anti-inflammatory compound
The uncleaved sulfasalazine is a folate antagonist, which would reduce theproduction of cells
And it reduces the production of IgA and rheumatoid factor IgM (both are
auto-immune antibodies by the way)
Mechanism of action is unclear:
Antimalarials (quinines)
Hydroxychloroqine and chloroquine are examples
Not very effective (only 50% response from patients)
Can cause remission, but the damage against bone can continue while taking
this drug
Luckily it's not very toxic though
Reduces lymphocyte proliferation
Inhibits IL-1 release (but it's thought to be not important)
Inhibits phospholipase A2, which is responsible for being along the
pathway of producing inflammatory mediators
Mechanism of action isn't clear either
Penicillamine
Avoid taking any iron, magnesium or calcium containing products
Has a few sites for chelation of metal ions
IgM rheumatoid factor decreases both in the blood and synovial fluid
Not anti-inflammatory
Again, mechanism of action isn't clear
Thought to be immune-mediated due to autoimmune reactions
Has toxic effects (limiting factor in treatment)
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Can be reversed with histamine administration
Pruritus (itchy mouth), rash and stomatitis
Drug fever (probably immune mediated), loss of taste, nausea and
anorexia can occur early in therapy
Membranous nephritis (kidney damage), myasthenia gravis,
polymyositis (chronic inflammation of the muscles)
MONITOR closely for symptoms
Start low, go slow (i.e. start on a low dose, and titrate up slowlywhile observing side effects)
It can also precipitate autoimmune reactions in the body
Azathioprine
Met this drug a lot now
Metabolised into 6-mercaptopurine
Apparently it's metabolised into thiopurine metabolites and incorporated into
the DNA to stop DNA elongation
This is in addition to inhibition of IMPDH to prevent purine synthesis (see
oncology)
Onset of action is slow (several months)
Cyclosporin
I'm pretty sure we've met this one as well (yay!)
See oncology module, lectures on immunosuppression and transplants
It inhibits calcinurin to prevent calcimodulin from binding, which prevents
IL-2 production
Remember: IL-2 production is required for clonal expansion of T cells
Anti IL-2 drug with a known mechanism of action
Effective when given in combination with other DMARDs
Nephrotoxicity and hypertensionHas some long-term adverse effects though:
Tumour Necrosis Factor alpha (TNF-alpha)
Stimulates neutrophils and macrophages so they move in and start
causing inflammatory damage
Plus stimulates T and B cells to grow due to macrophages being
stimulated to make IL-1
Very important role in inflammation
Inhibit the production or release
Prevent it from reaching the receptor
Stop the receptor from having its effects
We can either:
Administering monoclonal antibodies (e.g. infliximab) which is specific
against TNF-alpha
Administering soluble receptors which will also bind to it as well (e.g.
etanercept)
We can bind up the TNF-alpha by either:
Both are incredibly expensive
Besides, these things have a very long circulating half-life, only a fewinfusions are needed yearly
Both must be given IV or SC, as these are large proteins, they will not be orally
bioavailable as they are too large
Hypersensitivity reactions/infusion reactions
Increases chances of infections
Adverse effects include:
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TNF-alpha is again, very important in mounting an immune
response, if we prevent it from having it's action, then they become
partially immunocompromised
Plus since we have to pierce the skin for this, that also gives
increased chances of infection
Anakinra
The body has an endogenous IL-1 antagonist, anakinra is a recombinant form ofit
Competitive inhibitor at the IL-1 receptor
IL-1 receptor antagonist
Short half-life, must be administered daily SC (large protein as well)
Abatacept
Binds to CD80 and CD86
Prevents signal transduction between the antigen presenting cell and the T cell
to prevent activation
Due to the lack of proper activation, it reduces cytokine synthesis andinflammation
Rituximab
Used for CD20+ non-Hodgkin's lymphoma
We saw this one from oncology (part of rCHOP)
Reduced antibody production (IgM and other autoimmune
antibodies)
Interrupts the interwoven mesh that is the cytokine networks
Prevents activation of T cells and macrophages
Reduces further attacks by preventing B-cell mediated antigen
presentation (remember: their IgM can present)
Causes death and depletion of B cells
B cells can express CD20, and rituximab is an antibody which binds to it
Tocilizumab
Pro-inflammatory cytokine
Monoclonal antibody against IL-6 receptors
Last-line type drug which is used if the other DMARDs and TNF-alpha blockers
don't work
Could also be given if a person can't take methotrexate (remember, it causeshepatotoxicity and skin reactions)
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Joint anatomy (lab)
Types of joints
Least mobile
Uses dense fibrous connective tissue to connect between bones to
prevent movement
No movement mean there's no joint cavity
Sutures between the immature skull are an example
Fibrous joints
Fibrous cartilage
Tissue between the bones is held by semi-flexible cartilage
Allows some movement, and that's because the cartilage can be bent
Examples are the joints between the vertebrae
Cartilaginous joints
Most mobile, but least stable
Designed for smooth, frictionless movement
Has smooth articular cartilage
Joint space (or potential space) exists to allow free movement
Lubricated by synovial fluid produced from the synovial membranes
Synovial joints
Articular cartilage
The membrane is very delicate, it would not survive long if it were to be
present on the surfaces where they rub onto each other
Not covered by synovial membranes
Collagen arranged into a matrix
Composed of 'special' type 2 cartilage
Prevents drying out and crumbling away under pressure and shocks
Water also helps cartilage cushion joints against pressure and shocks as
well
Proteoglycans (aggrecans) embedded into the collagen are important, as they
will absorb and keep water within the cartilage
Subchondral bone is smooth, and it also provides an attachment
site for the cartilage
Must be supplied by diffusion from the synovial fluid or the blood vessel
rich sub-chondral bone which sits beneath the cartilage
Due to no vascularisation, it heals very, very slowly
Has no vascular supply
This is a good thing, otherwise we'd feel it each time our joints moved
But if the cartilage was to wear away, then the bones would rub onto
each other. The bones have nerve endings, so it hurts (osteoarthritis)
Has no innervation
Will synthesise collagen and aggrecans to maintain the cartilage
Pressure on the joint is required to physically squeeze nutrients towards
them, and to put pressure on them to secrete their contents
Which is why osteoarthritis can occur at older ages
Their function decreases over time, which leads to lower quality cartilage
Chondrocytes will sit in the cartilage
Bone
Pathology of arthritis and anatomy of the joints
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Organic (33%)- collagen is required to give it tensile strength (i.e. stops it
from being too brittle)
Inorganic (66%)- inorganic ions (hydroxyapatite and calcium phosphate)
for hardness and compression resistance
Strong connective tissue with organic and inorganic components
Compact (cortical) bone- dense bone which is good for resisting
compression and especially for tensile strength
Cancellous (spongy) bone- bone with struts called trabeculae, which will
align in the direction of stress. This is brought about by bone remodelling
Two types:
Synovium
One reason why it hurts like hell in an injury
Good nerve and blood supply
i.e. the membrane allows some substances to enter into the joint as
synovial fluid
Blood supply is required to produce synovial fluid, as it's a filtrate of plasma
Therefore it's responsible for lubrication of the joint
Hip
Between the illium of the hip bones and the head of the femur
Ball and socket joint
Adduction, abduction,
Flexion and extension
Circumduction
Rotation
Can produce many movements
i.e. since the amount of force it needs to bear is constant,
increasing the area reduces the force a single area needs to bear
The larger surface area is also good to distribute all the weight to reduce
the forces on the cartilage
Very stable joint as the head goes deep into the joint
Knee
Flexion, extension
Not really designed for rotation due to the shape of the condyles
Too much rotation will cause massive damage to the ligaments and
capsule and even the meniscii if the forces are great
Rotation is partially possible during flexion
Synovial joint with great mobility
Meniscus deepens the joint for increased stability
They prevent adduction and abduction
Two sets of ligaments (cruciate and collaterals) will keep it held in place
Inherently unstable as the condyles don't fit into each other
Dislocation in younger people due to increased activity
Fracture of the femur, especially at the head (but that's at the hip)
The most common injuries are:
For lubrication and keeping the bones in the joints respectivelySurrounded by synovial membrane and a capsule
Note: image from Gray's Anatomy, 20th edition. This image is in the public
domain, can be used without restrictions
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Spinal column
Overall movement of the spine is derived from the sum of the smaller
movements between the vertebrae
Flexion, extension and lateral flexion
Rotation is possible as well
The spinal column is made of several vertebrae connected by cartilage disks
7 cervical vertebrae
12 thoracic vertebrae
5 lumbar vertebrae
Need to remember their distribution:
Diaphragm
Laticimus dorsi
Erectus spini
Back muscles
There are some muscles which attach to the spinal column
Image is produced by the US government. Therefore it is in the public domain
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This (above) is a cervical vertebra, the joints between the vertebrae above and
below are less sloped to allow rotation to allow the head to rotate
Image from Gray's anatomy 20th edition
This (above) is typical for a thoracic vertebra
Ribs are attached here. Too much movement means the ribs will move
around and possibly damage the organs contained within
The lateral processes lock into each other, and the joints between the vertebrae
are much more sloped to restrict movement
Arthritis (guest 'lecture')
Osteoarthritis (OA)
Wear and tear of the joint usually caused by repeated use
Increased pressure on the joints
Obesity
This collagen makes up most of the articular cartilage
Type 2 collagen deficiency or mutation
Physical activity is important for cartilage health
Reduced physical activity
Specific types of joints are affected, like the knee and joints
between the fingers
Can be asymmetrical as one side tends to be used more
Repeated use of the joint
Other risk factors to consider are:
Due to spur formation
Along with hard, bony growths on the joints
The person can present with sharp bone pain
There is little space and bone contact which suggests the bones are
directly touching one another instead of being separated by cartilage
The bones may appear more dense at the points of contact as a responseto wearing down
If an X-ray were to be taken, then there would be little space between the
bones and the point of contact between the bones may appear more dense
Because the pain and stiffness will increase with joint use, it occurs mainly
at night
Stiffness mainly occurs in the evening, with minor stiffness in the morning
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Just analgesics I guess
No real treatments except for replacement
Rheumatoid arthritis (RA)
Inflammatory condition of the joint
Auto-immune attack against the tissues of the joint, especially the lining
(synovial membrane or synovium)
Female gender
HLA-DR4 (MHC), so it's genetic
Smoking is a major factor
Infections as some infections can trigger autoimmune reactions
General autoimmunity, as they tend to occur together
Risk factors are:
X-rays will show bone destruction near the corners of where the cartilage
should be, because the synovium is attached to the bone there
Converts the membrane into a pannus, which is a piece of destructive
inflammatory tissue which will attack other tissues and eat away at them
Unlike OA, the joint will be tender due to inflammation
Tends to occur in joints which aren't frequently used, like the joints of the
wrist
Since it's autoimmune, it tends to be symmetrical, occurring on both sides
of the body
Also unlike OA, the joints affected are different
Early treatment is very important to prevent progression of destruction of the
joints due to pannus formation
Granulomas with T cells and macrophages may be seen around the body
People can literally be frozen in place if damage is unchecked
Prevention of further damage to the bone and joint
Maintaining remission of inflammation to prevent damage
Treatment focuses on:
Patients with RA will likely be affected by another autoimmune disease
Patient with RA can have inflamed blood vessels due to general increases
in inflammation. This is associated with increased atherosclerosis and
cardiovascular disease
We also have complications to think about
Increased ESR (erythrocyte sedimentation rate)
Increased CRP (C reactive protein)
Inflammatory markers in the blood
Not very good for diagnosis though
Rheumatoid factor- autoantibody
Much better for diagnosis and for early detection
Anti-CCP- antibodies against citurilated proteins
Some of the diagnostic tests are:
NSAID + 1DMARD then
NSAID + 2 DMARDs then
NSAID + DMARD + biological
See workshop for details
The basic treatment is:
Spondyloarthritis
Ankylosing spondylitis is the most common cause
Inflammation of the ligaments holding the vertebrae together
Will cause fusion of bones between the vertebra resulting in a
Defined as inflammatory disease of the joints in the spine
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permanently disfigured spine
Associated with HLA-B27
Infection by an organism leads to an autoimmune reaction due to cross-
reactivity
Could be due to klebsiella
May be a reactive arthritis
Males in their early teens
Because this is an inflammatory disease as well
Focus on NSAID and anti-TNF-alpha but methotrexate won't work
Treatment is similar to that of RA, but they don't work 100%
T lymphocyte mediated instead
There's no identified antibody which is responsible for it (yet)
Septic arthritis
Need to treat fast to prevent joint damage
This is inflammation of the joint due to bacterial infection
Staphylococci or streptococci due to their presence on the skin
Could be another manifestation of gonorrhoea
Most common pathogens are:
The joint will become red, hot and swollen
Could separate it from RA on the basis of it affecting just one joint or one
side of the body (compared to many joints on both sides of the body in
RA)
But that's not diagnostic, need to take a sample (see below)
Would expect to see markers of inflammation in the blood as well
Will see pus filled liquid
Gram staining and culturing will give a definite answer
Best diagnostic method is to take a sample of the synovial fluid
Gout
See workshop (seriously, save yourself the waste of time this lecture has been, lucky I
wasn't here half the time)
Systemic lupus erythematosus (SLE)
Interesting because it targets the DNA and proteins of the nucleus (which
tend to wrap DNA)
Autoimmune disease
Around 35 years
Strong bias for women again
Causes the characteristic butterfly rash on the face, which is due to a
photosensitive reaction
It appears they have RA but...
There's no rheumatoid factor, no anti-CCP and not as much destruction
Affects many different tissues of the body, including the joints
Will set up inflammation in the kidneys which can lead to renal
inflammation and damage
If this occurs, need to consider chemotherapy drugs like
cyclophosphamide and mycophenylate mofetil to stop the immunesystem in its tracks
One large concern is the immune complexes are able to become stuck in the
kidneys
Except for that, there is very little that can be done about SLE