Let’s hear it for loperamide…

Let’s hear it for loperamide.
A drug that lets you postpone…
It acts on the plexus of Auerbach,
And decreases smooth muscle tone.

On the face of it, there is not too much explanation required for this one but there is at least one major issues that I would like to cover in this post. In addition there are probably a couple of minor ones as well, so let’s see how it goes.

Loperamide, is a μ-receptor agonist (see opioid terminology) that was first developed in the 1960s by Paul Janssen of Janssen Pharmaceuticals. The impact of opioids on the GI tract is probably as well known as their effect on pain and have certainly been taken for conditions like dysentry since the middle ages1, 2. Indeed, loperamide was preceded at Janssen by two other opioid based anti-diarrhoeals. Trails of loperamide were published in the early 70’s and it was marketed as Imodium, licensed and by the 80’s had become the most prescribed anti-diarrhoeal. In 2013 is was added to the WHO Essential Medicines list proving just how important a medication this is. 

Loperamide works by decreasing intestinal transit, slowing the passage of food through the bowel. The GI tract has two types of smooth muscle; circular smooth muscle arranged around the lumen (not unlike arteries and bronchi etc) and longitudinal smooth muscle arranged in strips along the length of the intestine. Between these layers of muscle sits the Plexus of Auerbach3 (or as you are more likely to see it referred to these days: the myenteric plexus), part of the enteric nervous system. This receives inputs from both the sympathetic and parasympathetic branches of the ANS as well as signals from the mucosa and muscle walls. Control of the contraction of these smooth muscle layers is controlled by a complex interaction4 between the ANS, the ENS as well as local mechanical stimuli, such as Bayliss and Starling’s law of intestines. While the exact details about how this is controlled is somewhat sketchy, what at is well known is that acetylcholine and substance P will constrict the gut, while noradrenaline and VIP will dilate the gut. Clearly, given the observations about opioids noted above, μ-receptors (as well as δ- and κ-receptors) are in the mix too. The μ-receptor has been reported on the longitudinal smooth muscle, the but actions of loperamide and endogenous opioids appear not to be direct muscular actions but rather are likely to be pre-synaptic, inhibiting the release of ACh and VIP thus decreasing intestinal motility. 

All of which brings us onto the pressing point of why do we get loose stools. Physiologically there are one of two problems here, irrespective of what the specific problem is. These can be broadly described as transit problems or osmotic problems.

Transit issues arise when passage through the gut is too fast to absorb sufficient amounts of fluid (and nutrients); it literally goes straight through you. Osmotic problems are due to a reduction in absorption. This leads to the retention of osmotically active electrolytes in the lumen, which in turn tends to hold fluid there and increase fluid loss5. There is some overlap here, because if absorption is reduced slower transit would allow more time for absorption and so would decrease the osmotic pull. This is why agents like loperamide work, because slowing transit will have an impact whether it is a direct or indirect transit issue.

The larger issue here relates to an old wives’ tale that I have heard a number of times. This is that you should not take anti-diarrhoeals as the loose stool is the body trying to clear the infection. Now, fair enough there are some cases where impeding the loss of infectious agents is not good and loperamide would be contraindicated. For example potential invading bacteria such as E. coli 0157 or Salmonella but also C. difficile where failure to clear is an issue. However, as appropriate as it is to clear these, that is not the cause of the diarrhoea. Just the use of the word “try” should make you uneasy as this is another example of a teleological argument, basing an action on its consequence rather than its stimuli.

In most cases infective diarrhoea arises from disruption of the mechanisms mentioned above. Norovirus, for example, appears to damage the microvilli on the epithelial cells and lead to hyperplasia of the crypt cells. The impact of this would be to decrease absorption and increase secretion, leading to an osmotic diarrhoea. It is not dissimilar for many bacterial infections, both E. coli and V. cholerae release endotoxins that lead to the hypersecretion of Cl from the crypt cells, again producing an osmotic diarrhoea while other infections or inflammation simply decrease the surface area for absorption. In these cases, slowing transit allows for more time to absorb water and solutes and so less watery stools and subsequently less dehydration. Since dehydration is the main factor in leading to diarrhoeal-related death6, this is why it is an essential medication.  

 

 

Footnotes

1. There is an excellent review of the μ-receptor pharmacology here. In case your interested my favourite opioid receptor is the ORL1. If you are going to be pedantic and insist upon a classical opioid receptor then it’s the κ-receptor.

2. Apparently there is an old saying amongst pain specialists: ‘God gave them two hands so that while one hand prescribes an opioid, the other will prescribe a laxative’. I cannot comment on that myself but this paper by Bril et al., thought it worthy of mention.

3. Some people are not keen on eponymous names. They point to inconsistencies in whether the name reflects the true discoverer, ethical concerns about the practices and motives of some and then there is the simple practical concern that these are not at all descriptive. The Plexus of Auerbach and its near neighbour, Meissner’s Plexus are perhaps better described as the myenteric plexus and the submucosal plexus. Personally I do not agree and I happen to prefer eponymous names, mainly because the term myelin sheath gaps as an alternative for the wonderful Nodes of Ranvier is just mind-numbingly awful. 

4. To give some idea about how complex, I have a four year old (2014) GI textbook which simply states the exact pathways are being elucidated. 

5. This is how osmotic laxatives such as polyethylene glycol work.  

6. WHO estimates more than 500,000 infant deaths per year from diarrhoeal disease making it the second largest cause of death in infants

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It doesn’t divide cleanly by action

It doesn't divide cleanly by action, 
Nor pharmacologically. 
Indeed the only true ANS distinction, 
Is anatomically.

I’ve been a bit lax in writing new posts for this for a while. There are many reasons for this, partly because I’ve been busy but also because some of the last posts tended to be more than just the short, snappy descriptions I started with. Today, I return to the short, snappy posts.

Like drugs and buffers, rules of thumb have a therapeutic range. That is to say that although there might be some truth in them, around the edges this no longer holds true¹. The distinctions between sympathetic and parasympathetic branches of the ANS are full of such fuzzy rules that I intend to point out the limits of how far they can go.

Can we divide them by action (or physiology)?

Whether we can does not really matter. “Fight or flight” and “rest and digest” are such common epithets for the two branches that you would have more luck getting people to stop talking about cheeseburgers or helipads². There are two problems with these. Firstly it sets the branches as antagonistic of each other, which is not always true. Secondly there are functions of each that are not included within these descriptions – is a more proteinaceous saliva a benefit during fight or flight? The same could be said for piloerection, certainly in humans but at the risk of crossing into comparative physiology³ this at least has an obvious advantage in hairy mammals. A cat with its hackles up is slightly more impressive than goosebumps.

So if they are not entirely about “fight or flight” or “rest and digest” are they at least physiologically antagonistic? Well, no. The parasympathetic branch controls the volume of salivary secretion in response to sight, smell or associated food stimuli4, but we have already heard that the sympathetic changes the composition of secretions. This is not antagonistic. Equally both branches have a role to play in the eye, with sympathetic leading to dilation of the pupil and the PNS focussing the lens.

 

Can we divided them pharmacologically?

Ok, so if cannot say that the SNS does these things and the PNS the opposite can we say that the SNS are adrenergic and the PNS is cholinergic? You guessed it. No.

Leaving aside that ganglia in both SNS and PNS use ACh at nicotinic receptors5 it does not even hold true at post-ganglionic receptors. Yes it is true that the PNS branch is cholinergic but not all sympathetics are adrenergic. Sweating and piloerection are controlled by these sympathetic nerves, which are not adrenergic but rather are cholinergic. As such, you cannot even say if it is cholinergic is it parasympathetic.

 

So, if they are cholinergic how do we know they are sympathetic and not parasympathetic? The answer is because of where they come from. This anatomical distinction does not require exceptions or clarifications because no sympathetic fibre, ever originated from anywhere other than the thoracic-lumbar region.

Screen Shot 2017-12-19 at 12.30.57

 

 

Footnotes

1) Think of i before e, except after c. Which is fine for a number of cases but to be fair exceptions to this are not hard to come by. Anything that has a long “a” sound such as weigh is always “ei”. As such there is continuation of the rhyme that goes on: unless it sounds “a” as in neighbour and weigh. Even taking this into considerations there are still many examples (such as science) that do not fit either. Still more do than don’t so it is a helpful rule of thumb, not a hard and fast rule.

2) The steak patty in a bun originated in Hamburg and was thus called a hamburger – it has nothing to do with ham. Beef burgers, cheeseburgers, lamb burgers, veggie burgers are all corruptions of this. Equally helicopter is formed of two roots but neither is heli nor copter. Instead its roots are helico and pter as in spiral wing.

3) For the record, I don’t want to cross into comparative physiology

4) Thanks to Ivan Pavlov

5) These are often referred to as “type 1” as oppose to type 2 at neuromuscular junctions but this is a slightly misleading concept itself. The nicotinic cholinergic receptor is a ionotropic receptor comprised of five sub-units arranged around a central pore. As such, with some 10 α sub-units, 4 β sub-units as well as a γ, a δ and an ε sub-unit then any two “type 1” receptors might be quite different in the sub-units that make them up.

Muscle Poems

May 8 2017
The increase in muscle perfusion
That occurs when work’s being done
Is locally driven, by paracrine factors
Like heat, pH and potassium

12 Dec 2016
Nicotinic or muscarinic receptors,
Which is which, you need to know.
Nicotinic in muscles and ganglia,
As ion channels they promote ion flow

28 Nov 2016
To understand the power stroke,
Requires rigours of the mind.
Without ATP,
Cross bridges remain rigidly,
And give rigor of a different kind.

18 Jul 2016
The reactive hyperaemia
Is endothelium-dependent, you know.
As blood rushes here,
The tangential shear,
Triggers eNOS and release of NO.

21 Mar 2016
Distribution of blood flow in exercise,
Drives tissue oxygenation.
Avoiding confusion, cerebral perfusion,
Remains stable by autoregulation.

11 Jan 2016
Smooth muscle is not all the same,
To think so is quite disingenuous.
It fulfils a number of aims,
Consequently it is heterogeneous.

Jan 25 2014
It may seem paradoxical,
This hypocalcaemic tetany.
Low Ca OUTSIDE the cell,
Disrupts transport as well,
And leads to increased Na entry.

Jan 18 2014
Nicotinic cholinergic receptors
Located to fit their function
Ions flow when bound, so they’re found
At ganglia & the neuromuscular junction

Jul 13 2014
The uterine smooth muscle,
Stays quiescent throughout gestation.
As placental progesterone levels fall,
So it increases uterine excitation.

12 Jan 2014
Muscles regulate contraction differently,
So heed what I have to say.
Striated muscles have troponin,
Smooth muscle has MLCK

8 Dec 2013
Myocytes stretched with preload,
Contract with greater efficiency.
I must point out,
So there’s no doubt,
This is different to contractility

10 Nov 2013
In the muscle powerstoke,
Cross bridges are the key.
To form them you need calcium;
To break them ATP

16 Oct 2013
Smooth muscle has no striations.
Nor troponin C.
But it can generate significant tension,
With 1/3 of the ATP.

 

Nerves & Neuro Poems

12 Dec 2016
Nicotinic or muscarinic receptors,
Which is which, you need to know.
Nicotinic in muscles and ganglia,
As ion channels they promote ion flow

21 Nov 2016
It’s intrinsic to the vascular bed;
Doesn’t need outside intervention.
That’s why it’s called “auto” you know.
I’m taking of autoregulation.
    

4 Jul 2016
Plasma hyperkalaemia;
The membrane potential disrupts.
Resting potential may rise,
Hard to repolarise
As there’s limited potassium efflux.

19 Jun 2016
“Look at my new micrograph.
Both markers there to be seen.”
Please keep in mind,
Some folks are colourblind
& all that I see there is green

22 Feb 2016
“An EPSP is excitatory;
I know physiology.”
I won’t comment on the latter,
But the former’s s a tautology.

14 Dec 2015
To regulate intracranial pressure
Monroe-Kellie Doctorine tells all
If the brain does swell
All is not well
So the blood flow in must fall

7 Dec 2015
During the action potential
Sodium enters the cell
Despite depolarisation,
The change in concentration
Of sodium is actually small

16 Nov 2015
Fight or flight vs. rest & digest?
Short vs. Long post ganglion?
To classify branches of the ANS,
Then look to their point of origin.

15 Nov 2015
It’s true for the ANS,
As it’s true for every one.
Exceptions exist for many a rule,
But especially a rule of thumb.

9 Nov 2015
Terminology in opioid pharmacology,
Is specific to what you relate.
Synthetically made; it’s an opioid.
Naturally derived; it’s an opiate.

2 Nov 2015
Feeling heat through sensory receptors
You need some way to react
Just like pain
It’s relayed to the brain
Along the spinothalamic tract

28 Sep 2015
Adrenaline OR epinephrine;
Using both seems poorly planned.
They act adrenergic receptors,
And are produced by the ADRENAL gland.

Aug 23 2015
Neuron depolarisation,
Requires an inward Na+ current.
The threshold potential,
Is so influential,
As those channels are voltage dependent.

Jul 27 2015
A homeostatic mechanism
Needs an input, effector & to sense
The output produced
May increase or reduce
But its cause isn’t its consequence

Jan 18 2015
Nicotinic cholinergic receptors
Located to fit their function
Ions flow when bound, so they’re found
At ganglia & the neuromuscular junction

Dec 28 2014
Fight/flight or rest & digest
ANS branches are antagonistic?
Not always so
There’s more to it, you know
That definition is overly simplistic

Dec 15 2014
Vascular innervation is sympathetic,
with parasympathetic on a rare few
Adrenoceptors are obviously there
but why are muscarinics there too?

Dec 8 2014
Na influx following threshold,
leads to depolarisation,
A big mV swing, but here is the thing,
It’s a tiny effect on concentration.

Nov 30 2014
Salivary secretions,
are induced by sight or smell.
Or any meal related stimulus,
Such as the ringing of the dinner bell.

Nov 24 2014
You can tell how much they like you
in an rapid resting heart rate
Not as invasive, but just as persuasive
is that pupils will also dilate

Nov 10 2014
Saltatory conduction,
occurs between myelin sheaths.
It hops away, between Nodes of Ranvier
and is quicker for taking such leaps.

Oct 27 2014
The key to the threshold potential
Is voltage-gated Na entry.
If EPSPs are enough,
to open channels up,
Na can rush in unchecked and free.

Oct 13 2014
The action potential overshoot,
Peaks at a certain point.
Further K+ loss
comes at electrical cost,
an inward gradient it cannot surmount.

Sep 8 2014
Action potentials spread everywhere,
So only forward may seem odd.
They cannot go back,
over previous track
Because of the refractory period

Aug 31 2014
It’s a popular misconception,
you only use part of your brain.
I wile away times, creating my rhymes
but my heart beats along just the same.

Aug 4 2014
Sympathetic nerves,
Rely on adrenergic transmission.
Keep this in your head,
Sweat glands cholinergic instead
and so they are the exception.

10 Jan 2014
Summation can be spatial:
At two places simultaneously.
Alternatively it can be temporal;
At the same place but consecutively.

24 Nov 2013
In the balance of potassium,
Be careful of the ECF;
Hyperkalaemia prevents potassium efflux,
Disrupts potentials and leads to death

19 Nov 2013
Ions move down gradients,
Into or out of the cell.
The voltage were electrical balances the chemical
Is known as the equilibrium potential

25 Oct 2013
‪Welcome to Southampton Brainy,
I’ve a place for you to stay.
With room for your cell body, axon
And nodes of Ranvier

17 Oct 2013
Oh Na/K ATPase,
Oh so influential.
Your net loss of +ve charge,
Contributes to membrane potential

Respiratory Poems

Jun 12 2017
Hypoxaemia and respiratory failure,
Are not one and the same.
Failure relates
to PaO2s below eight.
If above, then failure isn’t the name.

May 29 2017
The alveolar gas equation
Gives alveolar O2.
With this value in mind,
The Aa gradient you’ll find.
And gas exchange efficiency you can view.

Apr 3 2017
A PaO2 of 7 kIlo pascals,
Is enough to make you flinch.
As the idiots whine,
“Let’s redefine”,
So we’ll call it 1 pound per square inch.

Mar 13 2017
If you ascend to high altitude
Altitude sickness can be atrocious
It may offer some consolation (or not)
To know it’s respiratory alkalosis

Feb 27 2017
A forced expiratory measure,
Requires full inhalation.
It makes the airways more patent,
And provides the best exhalation.

Feb 20 2017
Buffers are weak acids
At equilibrium
The addition or loss of some proton
Is offset by changing this fulcrum

Feb 13 2017
The PaO2 represents,
Just a fraction of the O2 content.
Its importance you see,
Is what saturation would be,
As THAT accounts for some 98%.

Jan 2 2017
Hypoxic vasoconstriction,
Unique to the pulmonary tree.
It can occur on ascent to altitude,
Or as a consequence of COPD.

14 Nov 2016
Distribution of beta-recetors:
One heart, two lungs and all that.
Just keep in mind, this is streamlined
But as good a place as any to start

26 Sep 2016
Is it underventilation?
V/Q mismatch, a block or a shunt?
If you’ve ruled out these,
That only leaves,
Environmental to cause this ailment.

28 Aug 2016
In a respiratory acid base problem
The bicarbonate alone won’t tell
If there’s any metabolic compensation
Since its depends on CO2 as well
15 Aug 2016
A case of pulmonary embolism
And a large reduction in flow.
Despite normal ventilation
Blood redistribution
Means VQ ratio is actually low.

7 Aug 2016
Is it better to ventilate,
Breathing half as much but at twice the rate?
Of course it’s not
You’ve forgot
Each breath loses air to deadspace

27 Jun 2016
Bisphosphoglyceric acid,
Stabilises deoxyhaemoglobin.
It binds beta chains,
So its efficacy wanes,
In the fetus, where gamma’s more common.

5 Jun 2016
To maximise ventilation,
Breathe deep, at slow pace.
Rapid & shallow
Might produce the same air flow
But you’ll lose more to the dead space.

18 Apr 2016
Blood gases control ventilation
When they stray from the reference range
But this does not explain exercise
Where both are largely unchanged

4 Apr 2016
Training improves performance,
And reduces respiratory rate.
Don’t be confused,
Tissues are better perfused,
Reducing the amount of lactate.

14 Mar 2016
Blue with the cold I hear you say,
Want my diagnosis?
The reduced perfusion & increased extraction,
Has led to peripheral cyanosis.

7 Mar 2016
Flow through an artery or bronchi
Follows Ohm’s law, don’t you know.
Assuming a stable resistance,
A larger pressure gradient increases flow

29 Feb 2016
The PaO2 reference range,
Does not have an upper limit.
By 10.6 kPa, Hb’s saturated,
And availably is hardly infinite.

1 Feb 2016
The concept of hypoxic drive,
So often misunderstood.
If you think it kicking in,
Means CO2’s in the bin,
Then take a trip to high altitude.

18 Jan 2016
The pulmonary circulation,
Offers low resistance to flow.
It accommodates right cardiac output,
And keeps pulmonary pressures quite low.

28 Dec 2015
Hypoxia or ischaemia?
There’s a distinction you should know.
Both lead to low oxygen;
But ischaemia is only poor flow

23 Nov 2015
“It’s a cardioselective blocker;
Can be used in asthma” you boast.
A note of concern,
“Selective” is the term:
A property dependent on dose.
 

Aug 31 2015
Obstructive or restrictive?
That’s what you have to tell.
Obstructive has a low FEV1,
Restrictive, a low FVC as well.

Aug 17 2015
There’s evidence of hypoxaemia,
Is it V/Q mismatch or shunt?
Supplemental oxygen can distinguish,
Only mismatch will show improvement

Aug 9 2015
If the PaCO2 is low,
It doesn’t matter what the pH is.
There is clear hyperventilation,
That has produced a respiratory alkalosis.

May 4 2015
When perfusion exceeds ventilation
The extra blood flow is wasted
High ventilation
Can’t balance this equation
The blood’s already saturated

Mar 2 2015
That mischievous little bicarbonate,
It has two stories to tell.
It rises in metabolic alkalosis,
And in respiratory acidosis as well.

Feb 23 2015
The amount of gas that dissolves
On the partial pressure depends
Diving will dissolve more nitrogen
Coming up quickly gives you The Bends

Feb 16 2015
The dissolved oxygen content,
Is partial pressure dependent.
No matter what breathing you do,
The PaO2,
Will never exceed the environment.

Feb 9 2015
Assessing blood gases at high altitude
There’s only one plausible answer
Hypoxaemia may well be present
But not due to respiratory failure

Jan 11 2015
The Henderson-Hasslebalch Eq.
Can induce a look of pain.
All it explains, is the ratio must stay the same
If the pH is to resist any change.

Nov 17 2014
Ascent to high altitudes
Results in hypoxic hyperventilation.
The upshot of this,
is respiratory alkalosis
& centrally driven CO2 retention.

Sep 15 2014
Biphosphoglyeric acid,
binds the beta chains of Hb.
Of course not the same, fetus has delta not beta chain,
so here it can’t effect affinity

Jul 20 2014
A saturation of 50%,
means that half your Hb are empty.
Wait, I implore!
It’s not 2 out of 4,
as each subsequent oxygen increases affinity.

Jul 1 2014
Oxygen is vital,
without it you’d be dead.
But this is not ventilation’s primary concern,
that is acid base balance instead.

Jun 22 2014
Most CO2 is carried as HCO3-.
A gas or by Hb what remains.
At first it may seem, it’s bound to the haem,
But in fact binds the globin chains

Jun 15 2014
The Henderson-Hasslebalch equation,
tells you all you need to know.
The pH can always be corrected,
by restoring the acid to base ratio.

30 May 2014
Raised CO2 is hypercapnia,
but it tells you more than this.
It is by definition hypoventilation
and respiratory acidosis.

6 Apr 2014
Three cheers for J.S. Haldane,
and the effect that bears his name.
A stronger acid, oxy-Hb
liberates protons and CO2 from the globin chain.

17 Mar 2014
The Bohr effect is beautiful;
Perfect symmetry.
The uptake of CO2 into the erythrocyte
enhances O2 delivery.

2 Mar 2014
Anaemia is a low haemoglobin,
and may make you hypoxic.
But there is rarely enough
of that carrying stuff
For you to also appear cyanotic.

3 Feb 2014
Haemoglobin is the workhorse
And its saturation is the key;
The PaO2 informs this
As they interact sigmoidally.

26 Jan 2014
The PaO2 is important,
but this only represents;
the dissolved O2 component
and so a fraction of oxygen content

19 Jan 2014
In acid base balance,
Acidosis requires compensation.
Metabolic acids stimulate carotid chemoreceptors
Producing hyperventilation.

6 Jan 2014
As hydrogen binds to globin chains
It makes O2-haem binding less likely.
Since respiring tissues release H+,
so it increases oxygen delivery

30 Dec 2013
A high respiratory rate, or tachypnoea,
is just that in any situation.
But so you know,
the PaCO2 must be low
for it to be hyperventilation.

17 Oct 2013
‪When O2 binds to haemoglobin,
it’s called an OXYGENATION.
No loss of electrons occurs
so it can’t be an OXIDATION

16 Oct 2013
Hypoxia & cyanosis
You use these interchangeably
But they mean something distinct
So are spelt quite differently

Angiotensin is vital in pregnancy…

 

Angiotensin is vital in pregnancy
For blood to the fetus to be shunted
It drives the volume expansion
But its pressor responses are blunted

Last weekend it was Mothering Sunday, which prompted my to write this little number in honour of my mother1.

With the onset of pregnancy there are a number of haemodynamic adaptations that occur in the maternal cardiovascular system. In general, these adaptations occur in order to meet the additional metabolic demands on the mother and sustain the growing fetus. Indeed if you think about it, the mother now has to perfuse a whole new, metabolically active organ during gestation2. As a result these haemodynamic changes are vital for a successful pregnancy. The failure of these adaptations to fully occur may reduce blood flow to the fetus, challenging fetal development and possibly leading to maternal complications.

Occurring very early in gestation, the first adaptation to occur is a substantial fall in total peripheral resistance. Indeed, occurring as early as it does, the fall in peripheral resistance is vital and is thought to drive the subsequent adaptations.

Following the fall in total peripheral resistance there is a large increase in maternal plasma and blood volume, driven by increased Na+ reabsorption and erythropoiesis. Subsequently, as pregnancy develops, there is a marked increase in cardiac output via an increase in stroke volume and heart rate. The increased blood flow to the uteroplacental unit in pregnancy correlates to the increases in cardiac output and plasma volume highlighting the importance of these haemodynamic adaptations to a successful pregnancy.

Angiotensin II (Ang II) is the active part of the renin-angiotensin system3. Ang II is a potent vasoconstrictor and also has a role in Na+ balance directly and via the stimulation of aldosterone. During pregnancy, oestrogen increases plasma concentrations of renin, angiotensinogen, Ang II and aldosterone4. It is due to these oestrogen-mediated increases in Ang II and aldosterone that drive Na+ retention and plasma volume expansion.

Screen Shot 2017-03-30 at 00.05.21

The decrease in peripheral resistance is in part mediated by an imbalance in the vasoconstrictor/vasodilator pathways, not just that of Ang II. This too may involve the increase in circulating oestrogen. By early in pregnancy the vasopressor response of Ang II is markedly attenuated; whilst similar responses are see to catecholamines such as noradrenaline and phenylephrine. This is matched by enhanced endothelium-dependent vasodilatation via the increased release of endothelial-derived relaxing factors such as nitric oxide (NO), prostacyclin (PGI2) and the endothelium-derived hyperpolarising factor(s) (EDHF)5.

Screen Shot 2017-03-30 at 00.36.14
Constriction and dilatation in non-pregnant (open circles) and pregnant (filled circles) arteries. See the blunted constriction to phenylephrine and enhanced endothelium-dependent vasodilatation to ACh. 

The increased release of NO, PGI2 and EDHF during pregnancy is linked to circulating oestrogen. The influence of oestrogen on vasoconstriction and vasodilatation can be observed through the normal menstrual cycle with NO, PGI2 and EDHF-mediated vasodilatation all waxing and waning through the duration of the cycle. Not only does this increase vasodilatation, but it also goes some way to explaining the attenuated response to Ang II. For Ang II, it is the increased prostaglandins that appear to be particularly important for the blunted response, but teasingly this appears to be independent of oestrogen (or progesterone).

So there you go, Ang II (and aldosterone) drive plasma expansion but the blunted vasopressor response of Ang II is vital for the initial drop in peripheral resistance in early pregnancy.

 

 

  1. It is not true to say this was in place of a card, but I did subsequently forget to get one.
  1. Ok, fair enough, obviously the uterus was there prior to conception but it was hardly pulling the same proportion of blood flow. I am generally referring to the conceptus as a whole here.
  1. OK, there are a number of active angiotensin peptides including; Ang III, Ang IV, Ang 1-7 etc.
  1. The increased erythropoiesis however, is due to the erythropoietic effect of progesterone not oestrogen
  1. I think there is a distinction to be made about whether this is a name (there is an EDHF) or whether it is a description. There is more than one factor that is derived from the endothelium and hyperpolarises the underlying smooth muscle, but not all fit the characterisation for the original EDHF.

Deep in the placental villi…

 

Deep in the placental villi, 
Across which nutrients are passed. 
It is, the one and only... 
Syncytiotrophoblast!

I’ll hold my hands up straight away and say this is prompted primarily by a desire to fit “syncytiotrophoblast” appropriately into the metre of a verse. Rather bizarrely, two separate placenta related christmas carols1, 2 were brought to my attention this festive period, so it seemed fitting to carry this on.

So given this reasonably low target, how am I going to take this a bit further in a blog? Easy, let’s think about the syncytiotrophoblast in more detail and pun wherever possible.

The syncytiotrophoblast is an epithelial layer in the placental villi that separates the maternal blood from the fetal capillaries. For nutrients to cross from mother to fetus (or indeed fetus to mother), they must cross the syncytiotrophoblast by one of a range of different transport mechanisms. This is a frightfully complicated as you can see in this paper here3.

 

What is cool about the syncytiotrophoblast is suggested in its name – “syn” and “cytio” from the Greek meaning together and cell4. Yes, it is a single, giant, multinucleated cell. It is a true syncytium, one giant cell created by the fusion of smaller single nuclear cells5, 6.

So when I said “the one and only” – I meant it in more ways than one.

 

 

 

 1 Carols in the loosest possible sense you understand

 

2 Since you ask, here they are. The first was from a group of students who rather enterprisingly made this

"Spiral arteries from mother’s womb
Bearing gifts so baby can bloom
Through placenta, they must enter

Or baby will be doomed"

“O great placenta, it’s the boss
Lets the nutrients across
If you can fit, you might make it
Through to feed the foetus”

"Oxygen to offer have I
Crosses when carbon dioxide is high*
Passive diffusion, make no confusion
Like in alveoli"

"O great placenta, it’s the boss
Lets the nutrients across
If you can fit, you might make it
Through to feed the foetus"

"Glucose is mine, it’s food for the brain
Crosses to baby time and again
Feeds the placenta, only can enter
Through GLUT1s in the membranes"

“O great placenta, it’s the boss
Lets the nutrients across
If you can fit, you might make it
Through to feed the foetus"

"Mother’s blood has IgG
Gives passive immunity
Transcytosis, you should know this
Has to cross actively"

"O great placenta, it’s the boss
Lets the nutrients across
If you can fit, you might make it
Through to feed the foetus"

"Cortisol cannot enter
Broken down in the placenta
Betamethasone, you must go alone
Help lungs grow like they’re meant-ta"

"O great placenta, it’s the boss
Lets the nutrients across
If you can fit, you might make it
Through to feed the foetus"

In case you are wondering I have quoted directly, since I know there is no “o” in fetus. Then again, that’s me; I can help but find fault with things, however beautiful they may be.

 

The second was from the twitter feed of the excellent I-Heart-Histo ‏‪(@IHeartHisto), that I have captured here

screen-shot-2017-01-09-at-16-13-06

 

3 As much as it pains me to promote it, this paper is by my friend and colleague. Yet again I cite him while his own Facebook page (which is worth a read if you are interested in placentas) never returns the favour. In fact many months ago on this page I lamented thus: “Since I am an occasional member of the group, he had promised to link to me on there but at the time of writing this has not happened.” Well it still has not happened…

4 Well, strictly speaking cyto is the Latinised version of the greek kytos meaning box or container but it is also the name of a son of Zeus and the nymph Himalia.

5 Some people would say that the heart with its intercalated discs between cardiomyocytes is a syncytium; but while it might function as a syncytium (a functional syncytium) it is not a true syncytium.

6 Since this is the case, you might wish to ponder how you can have paracellular transport?

 

In My Day (Part 2)

So, having set questions here I have now provided some answers.

In addition to my questionable statements about me and me undergraduate days, I also alluded to two further cultural events which may or may not be familiar to you. These can be talked of freely amongst my peers, as I know they will know the reference points, you on the hand may not and this creates a gap between us.

So to bring you up to speed…Some 29 years ago, on the 15th of October 1987, Michael Fish famously told the viewers that there would be no hurricane in the UK. To say he was wrong was an understatement. You can watch the forecast and the aftermath here. No one has ever let him forget it.

You can also watch Monty Python’s Four Yorkshiremen here, and you’ll see why I wanted to avoid pretending everything was harder/better in my day.

 

Enough about those, what about my statements?

  1. The majority of people I call friends today, I met during my undergrad degree

True. I enjoyed my time at university so much I never actually left

  1. I had hair down to my shoulders in my first two years

False. I had cut it off by the time I started

  1. I won a karaoke competition in the Union

False. For soooooo many reasons.

  1. I saw baby pigeons

True. Once they have fledged they just look like pigeons

  1. I played full back for a university Gaelic football team

False. It was more of a centre half forward and even then more of a kick around

  1. I developed a pleasingly tasty punch.

True. If you allow some leeway on the subjective notion of “pleasingly tasty”

  1. I submitted all my coursework at the last minute

True. It wasn’t a good idea but deadlines do tend to invite that sort of behaviour.

  1. I worked as a chef at the weekends.

True. If you are again willing to be flexible in your definition of a “chef”

  1. I could only revise for a maximum of 60 minutes before stopping – much to the irritation of everyone I have ever studied with.

True.  

  1. I discovered I have no patellar reflex.

True.

  1. I was involved in a gambling bidding war with the Vice Chancellor.

False. I was a post-grad student when I did that…

  1. I still use some of those textbooks bought for the course.

True. Voet & Voet Biochemistry is a superb textbook

  1. I got the second highest marks in the year.

False. (But in what direction?)

  1. I still speak to my old tutors.

True. I see them occasionally at conferences and say hello

  1. I was elected president of the Biosoc

False. I was never elected; I merely assumed power in a bloodless coup d’état

  1. I experimented with opioids and cocaine

True. I was looking at the effects of the (then) novel opioid nociceptin and its ability to potentiate electrically-evoked contractions of muscle. This effect was quite similar in magnitude to the effect elicited by the inhibition of uptake 1 by cocaine, so cocaine was used to compare.

  1. I was (on more than one occasion) mistaken for a 35 year old.

Alas, this is also true

Statements about the course and general things

  1. We did not have email.

To all intents and purposes this is true. I received an email account at some point (the password was teleost2, but I have no idea what the address was) but this was optional and I don’t recall receiving email from the faculty. Each of my friends (see above) have confirmed this.

  1. All my project work & dissertation work was stored on a device, the capacity of which would be insufficient to hold a single jpeg you text to your friends.

True. I saved all my work on a 3.5” floppy disk that can hold 1.1-1.4 Mb. I had several of these, not due to the size of the files but because they were always corrupting and multiple back-ups were needed.

  1. No one had mobile phones

Again, to all intents and purposes this is true. In reality it is not quite true as my friend got a pay-as-you go phone which was the best part of £100. This might not seem a lot, but when I say it was a phone I mean just that all it could do was phone. So rare were mobile phones, that when giving the number out to young ladies on a night out, no one would accept it as they thought it was just a fake. Yes, it was unusual to have a mobile phone, we made plans and stuck to them.

  1. There are few pictures of me from this time (see previous post) because no one carried a camera around expect for very special occasions

True. When mobile phones did become more widespread it was some time before they could access the internet or take photographs. This means a separate camera was required. Fair enough, but this camera would also be film and not digital. So this means taking out another piece of equipment, which can only take 24/32 photos per roll of film. Once you had taken them you would need to get the developed and printed (at cost) and then show them to people in the shot. In the vanishingly rare circumstance that would see me bring a camera, there is a subsequent and equally vanishingly rare event that I would use that to take a picture of myself. You could not simply take 50 odd shots and then stick them all on Facebook.

  1. Everything from lecture changes to tutorial groups, from notes to exam results were posted on the year notice board for all to see.

True, we had no email remember. Everyday we’d swing by the noticeboard of the appropriate year group and see if anything was happening.

  1. The Union sold beer at £1.50 per pint, a good 30 p cheaper than most other venues.

True, it was also £3 to go to the cinema on Monday evening

  1. Each year required the purchase of new textbooks at ~£30 a piece.

True, if you accept the term required. There was no internet to speak off and you needed some resource. My friend and flatmate (a student of English) bought his course text of Jane Eyre for 35 p in the charity shop that we lived above.

  1. There was no associated webpages, no student consult no free multimedia disk options with any of those.

True. Again there was no internet in the sense you think of. When you bought a book all you got was a book.

On purchasing my copy of Voet & Voet Biochemistry I was automatically given a student discount. “Am I that obviously a student” I remarked. “Well,” she replied “who else would be buying this?”

  1. I had about 35 hours of contact teaching per week (mostly labs).

True. My flatmate from above had three hours and he did not go in for two of those. Some people say it is important to meet people outside your course, but sometimes their experiences can just be upsetting.

  1. The only audiovisual equipment in use was the overhead projector.

True. 95% of my lectures involved the lecturers putting up figures/diagrams on the overhead projector and talking about them. Some just put up text and others did not even do that.

  1. There was no blackboard, no powerpoint, no nothing.

True. Only one member of staff used Powerpoint for which they brought their own data projector. If no one was using it there would have been little need for an online repository for lectures and many of us had limited use/access to the internet anyway.

  1. If you missed a lecture you had to ask your friends (or the girl with the neat/legible handwriting) for a copy of their notes and try to reconstruct the lecture with your textbook.

True. Following on from above, in most lectures I spend my time scribbling down what my lecturers were saying. If absent you have to find out what you missed and so you needed someone else’s scribbled notes. Crucially, for this to work, and before you could decide whether their notes made sense or not you had to actually read them. Neat handwritten notes were rare in my circle of friends, save for a few.

  1. It was actually impossible to get 100% (20/20)

True. My friend and I wrote a perfect lab report only to score 19.5/20. We were docked half a mark for not showing our working clearly because we combined two calculations into one step. Decades on, this still touches a nerve.

  1. Each year the bottom ten per cent of the cohort were failed.

False. Of course not.

 

 

In My Day (Part 1)

Last year, I was approached via social media by my students and asked to contribute a blog post for their website. Since I have been lax in updating this site, I shall simply steal that post and reproduce it here.

It should be pointed out though, that this was not intended to be a physiology post but rather a bit of a biography about me and my own university days. So here it is.

 

A peculiar thing working with young people as yourselves is that you never get old. Of course you (the individuals) get older and move on, but the next year(s) I’ll still be in front of another cohort rehashing the same old lines. It is like “The Picture of Dorian Gray” in reverse, I get older despite a never-ending sea of fresh faces are sat in front of me.

The other thing is with each passing year, I get less and less with “it”. Nowhere was this more evident than at a recent Medsoc quiz music round, where even your “oldies” were too new for me. It was painful. There is a slightly more serious (and indeed educationally serious) aspect to this and that is the disconnect between my experiences and expectations and yours. This is both cultural (see the quiz), but also importantly technological.

It is true to say that I was once an undergraduate student like you are now. That said, my experiences in the previous millennium are quite different from yours in a myriad of ways, as they were for my tutors before me. Not too long ago, and within a decade of me finishing my first degree, I was asked where I saw physiology teaching in the next ten years. I side-stepped that question, because so much has changed since my own undergraduate experience (and even within my time teaching here) that any prediction would have been as accurate as a Michael Fish weather forecast (cultural reference claxon)!

So, to stop this turning into Monty Python’s “Four Yorkshiremen” (cultural reference claxon), I instead invite you to take part in a true/false quiz about my time as an undergraduate, so that you might have a better idea of where I am coming from. Each of these statements is either wholly true or an outright lie and I make no comment on the proportion of each (they could all be true, all be lies or anywhere in between).

 

Statements about me as an individual

  1. The majority of people I call friends today, I met during my undergrad degree
  2. I had hair down to my shoulders in my first two years
  3. I won a karaoke competition in the Union
  4. I saw baby pigeons
  5. I played full back for a university Gaelic football team
  6. I invented a pleasingly tasty punch.
  7. I submitted all my coursework at the last minute
  8. I worked as a chef at the weekends.
  9. I could only revise for a maximum of 60 minutes before stopping – much to the irritation of everyone I have ever studied with.
  10. I discovered I have no patellar reflex.
  11. I was involved in a gambling bidding war with the Vice Chancellor.
  12. I still use some of those textbooks bought for the course.
  13. I got the second highest marks in the year.
  14. I still speak to my old tutors.
  15. I was elected president of the Biosoc
  16. I experimented with opioids and cocaine
  17. I was (on more than one occasion) mistaken for a 35 year old.

Statements about the course and general things

  1. We did not have email
  2. All my project work & dissertation work was stored on a device, the capacity of which would be insufficient to hold a single jpeg you text to your friends.
  3. No one had mobile phones
  4. There are few pictures of me from this time (see previous post) because no one carried a camera around expect for very special occasions
  5. Everything from lecture changes to tutorial groups, from notes to exam results were posted on the year notice board for all to see.
  6. The Union sold beer at £1.50 per pint, a good 30 p cheaper than most other venues.
  7. Each year required the purchase of new textbooks at ~£30 a piece.
  8. There was no associated webpages, no student consult no free multimedia disk options with any of those.
  9. I had about 35 hours of contact teaching per week (mostly labs).
  10. The only audiovisual equipment in use was the overhead projector.
  11. There was no blackboard, no powerpoint, no nothing.
  12. If you missed a lecture you had to ask your friends (or the girl with the neat/legible handwriting) for a copy of their notes and try to reconstruct the lecture with your textbook.
  13. It was actually impossible to get 100% (20/20)
  14. Each year the bottom ten percent of the cohort were failed.

 

You can find the answers to these questions here.

Bisphosphoglyceric acid…

“Bisphosphoglyceric acid,
Stabilises deoxyhaemoglobin.
It binds beta chains,
So its efficacy wanes,
In the fetus, where gamma's more common.”

There are some facts that are helpful and some that are not. For example, did you know that fetal haemoglobin (HbF) has a higher affinity for oxygen than adult haemoglobin (HbA)? To all intents and purposes this is both true and useful. On the other hand, did you know that purified HbA (i.e. not within erythrocytes) has a stronger affinity to oxygen than HbF? This is actually true but could be considered of limited value because of its artificial nature and its apparent contradiction to normality. So, if you want to take facts as independent entities, unrelated to each other, then the first one is for you. If you want to understand the first one, then you need more facts and the second one helps us on that way.

If we consider the P50 (the partial pressure of oxygen that relates to a Hb saturation of 50%) of the dissociations curves from HbA, HbF and purified HbA we see that they are approximately 2.9 kPa, 2.5 kPa and 1.6 kPa respectively. What this says is that there is something in the red cell that decreases the oxygen affinity to HbA (1.6 kPa – 2.9 kPa) but which has less of an effect on HbF. Step forward 2,3 bisphosphoglyceric1 acid (2,3 BPG).

Screen Shot 2016-07-04 at 22.10.45

Figure showing the oxygen dissociation curves for HbA, HbF and purified HbA. Both their wonderfully sigmoidal curves and a bar chart of their P50s

Of course, 2,3-bisphosphoglyceric acid will be familiar to all of us as the isomer of 1,3-bisphosphoglyceric acid – the product of reaction 6 (the GAPDH one) in glycolysis. Ring any bells? Of course glycolysis is particularly important in the erythrocyte and this intermediate is converted by the enzyme BPG mutase, moving the phosphate from carbon 1 to carbon 2 on the glycerol chain.

Screen Shot 2016-07-04 at 22.49.08

Conversation of 1,3 BPG to 2,3 BPG by BPG mutase

How BPG works is that it sits in the central cavity of the deoxy-Hb and forms hydrogen bonds with a couple of cationic amino acid residues (lysine & histidine) and the N-termini of the β globin chains. By cross-linking the two β chains, BPG stabilises the deoxy conformation of Hb. As discussed previously, oxygen binds to Hb in a cooperative manner. As each oxygen binds to the haem group, it alters the positioning of the phorphyrin ring, which, in turn, alters the conformation of the whole structure. This has two effects, one is to make the additional haem groups more accessible but the other is to alter the size of the central cavity and make BPG binding less strong.

Screen Shot 2016-07-04 at 22.52.10

All haemoglobins are tetramers, consisting of two pairs of globin chains. Both HbA and HbF contain two α chains and two β chains. The only difference between HbA and HbF is that while HbA has two β chains, HbF has two γ chains instead. Importantly, while the β chain has those important, cationic histidine residues the γ chains have uncharged serine residues in the same place. The upshot of this that BPG’s binding is weakened, meaning the deoxy state is less stable and so there is an increased affinity to oxygen. Which is exactly what I said above…

Footnotes

1: This use to be called diphosphoglyceric acid but at some point became bisphosphoglyceric acid. Quite why the Greek di became the Latin bis I have no idea and since they both mean the same I am unsure why the need to change. It is fair to say this occurred before my time since my UG copy of Voet & Voet (and excellent Biochemistry text, and helpful for this post) uses BPG.