musculoskeletal v0.2

7/31/2019 Musculoskeletal v0.2

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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



23/25

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

musculoskeletal v0.2

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