Management of COPD

I've written a shit-ton about COPD before, but in this post I'll be talking about therapies to treat it in a bit more depth.

Previous posts on COPD:

• COPD
• Respiratory Pathophysiology 1
• Respiratory Pathophysiology 2
• Respiratory Pathophysiology 3

A bit more on classification of COPD...

First, just a couple of notes on COPD classification that I haven't spoken about before. Two different sets of criteria that can be used for classifying the severity of someone's COPD are the GOLD criteria and the COPD Assessment Test (CAT). The GOLD criteria is based off someone's FEV₁/FVC ratio, with 1 (mild) being >80%, 2 (moderate) being 50-80%, 3 (severe) being 30-50% and 4 (very severe) being <30%. The CAT is basically a questionnaire that asks questions about quality of life related stuff, like "When I walk uphill I am not breathless" vs. "When I walk uphill I am breathless." A CAT score of more than 10 indicates that COPD may be interfering with quality of life.

Treatment varies depending on COPD severity. Someone with low GOLD and CAT scores may only require short-acting as-needed bronchodilators. As the severity increases, long-acting beta-agonists and muscarinic antagonists may be required.

Treatments for COPD

Beta-agonists

Beta-agonists activate Gs, which activates adenylate cyclase, which converts ATP to cAMP. Aside from the relaxation effects of cAMP discussed here, cAMP can also inhibit MLCK, which is important in contraction of smooth muscle (like the muscle of the airways). Beta-agonists come in two main varieties: short-acting beta-agonists which are given as needed, and long-acting beta-agonists which are taken once daily (such as indacaterol) or twice daily (such as salmeterol or eformeterol).

Why aren't short-acting beta-agonists able to be taken more often? Unfortunately, short-acting beta-agonists may increase the risk of cardiovascular adverse effects, including myocardial infarction and stroke. Hence, they are only taken as needed.

Muscarinic antagonists (anticholinergics)

Muscarinic antagonists, as their name suggests, act on muscarinic receptors. There are three main kinds of muscarinic receptors in the lung: M₁, M₂ and M₃. M₁ receptors facilitate transmission of acetylcholine from one nerve to another. M₂ receptors are located near the end of the neuron and limit further ACh release if there's already a lot floating around in the neuromuscular junction. There are also M₂ receptors on the airway muscle cells, which help to counteract muscle relaxation. Finally, M₃ receptors on the airway muscle are responsible for contraction of the smooth muscle cells.

Many muscarinic antagonists, such as tiotropium and aclidinium bromide, are long-acting and are taken once daily. They preferentially act on M₁ and M₃ receptors. Adverse effects of these drugs include an increased risk of dry mouth and urinary retention.

Theophylline

Theophylline has a modest effect on FEV₁ and FVC, but it's not used very much because it has a very small therapeutic window (i.e. it's hard to get the dose just right so that it has an effect without being toxic).

Roflumilast

Roflumilast is a relatively new drug used to treat COPD. It is a PDE4 (phosphodiesterase 4) inhibitor that is taken once daily. Unfortunately, it has some unpleasant side effects, such as nausea and vomiting.

Anti-oxidants

Antioxidants, such as N-acetylcysteine and carbocysteine, are also being investigated as potential therapies.

Nutrition

Excess and low weight are both associated with increased morbidity. In the case of excess weight, obesity can increase the work of breathing and predispose to sleep apnoea.

Statins

Statins, which are drugs primarily used to treat high cholesterol, have also been investigated as potential COPD therapies. Why statins? Well, they lower lipid levels and have anti-inflammatory and anti-oxidant effects, so there's a chance that they might help COPD patients.

Lung volume reduction surgery (LVRS)

Obviously, this is a more "extreme" way of treating COPD. It literally just involves removing the more severely affected areas of the lung, improving lung elastic recoil and diaphragmatic function. So far surgery does not appear to improve chances of survival, but it does improve exercise capacity.

Antibiotics

At one stage antibiotics were looked at to prevent exacerbations, but current evidence does not support this practice due to problems like antibiotic resistance, etc. Antibiotics are still used in certain kinds of exacerbations, though.

Oxygen therapy

This basically involves giving the patient a tank full of oxygen that they need to cart around with them all day. 'Nuff said.

Cellular therapies

There has been some research into stem cell therapies to treat COPD, but by the sounds of things it is very much in its infancy.

Co-morbidities of COPD

Some conditions that are comorbid with COPD include cachexia (muscle wasting), pulmonary hypertension, ischaemic heart disease, osteoporosis, anxiety and depression.

Pulmonary hypertension is seen in around 50% of patients with severe emphysema. Unfortunately, there are no pharmacological therapies to treat it. It can be diagnosed by using echocardiography, but sometimes this diagnostic tool is not as effective if there is hyperinflation.

Osteoporosis is an issue not only due to the disease itself, but due to other factors such as inhaled corticosteroids, reduced muscle mass due to immobilisation (hard to exercise when you can't breathe) and so on.

Exacerbations

Exacerbations are basically a change in baseline dyspnea, cough and/or sputum. These often happen due to factors such as bacterial and viral infections. There are some biomarkers which can hint at whether the cause is bacterial or viral: sputum IL-1b is the best predictor of bacterial exacerbation, whereas serum CXCL10 is the best predictor of viral exacerbations. Treatment includes antibiotics (for bacterial infections), glucocorticoids, and ventilatory assistance.

Synthesis

In my previous posts, I've spoken a lot about how things are broken down. This will be my first post about synthesis, specifically the synthesis of glucose, glycogen and fatty acids.

Describe the reactions and regulation of anabolism of glucose (gluconeogenesis from various substrates) and fatty acids

Anabolism of Glucose - Reactions

In this post, I'm only going to cover gluconeogenesis, or formation of glucose from a source other than glycogen. Glycogen is just a chain of glucose, so getting glucose from glycogen is too easy- all you need to do is break down the glycogen chain. I've detailed both the breakdown of glycogen to glucose, as well as the synthesis of glycogen from glucose, in an earlier post.

Anyway, back to gluconeogenesis. Substrates for gluconeogenesis include pyruvate, lactate, other sugars (such as galactose and fructose), glycerol and amino acids. Note that Acetyl CoA cannot undergo this process.

For the purposes of this post, we're going to focus on pyruvate. Conversion of pyruvate to glucose is essentially the opposite of the glucose -> pyruvate pathway (a.k.a. glycolysis), which I've explained here. However, as I mentioned in that earlier post, some of the steps in the glycolysis pathway are irreversible, so we need other enzymes to bypass them. The steps that require bypassing are the following:

1. Pyruvate --> Phosphoenolpyruvate (PEP)
2. Fructose 1,6-bisphosphate --> Fructose 6-phosphate
3. Glucose 6-phosphate --> Glucose

The first of these reactions, the conversion of pyruvate to PEP, actually requires two enzymes. Firstly, pyruvate carboxylase converts pyruvate, bicarbonate and ATP to oxaloacetate, ADP and phosphate. In the second step, PEP carboxykinase converts oxaloacetate and GTP to PEP, GDP and CO₂.

The second reaction is a lot simpler: fructose 1,6-bisphosphatase converts fructose 1,6-bisphosphate into fructose 6-phosphate. Energy is released in this step (though this doesn't make up for all of the energy required in anabolism, as I'll get to in a bit).

The third reaction is also relatively simple: glucose 6-phosphatase converts glucose 6-phosphate into glucose.

Overall, this is a somewhat energy-hungry process. Two pyruvate molecules are required for every glucose molecule, as pyruvate has 3 carbons and glucose has 6 carbons. Two ATP molecules and one GTP molecule are required for each pyruvate molecule (conversion of pyruvate into PEP requires ATP and GTP, as mentioned above, plus conversion of 3-phosphoglycerate into 1,3-bisphosphoglycerate requires ATP). Hence, the overall energy requirement per molecule of glucose is 4ATP and 2GTP, and since 1 GTP ~ 1 ATP, this can be simplified to 6ATP. Here's the overall equation:

2 Pyruvate + 6 ATP --> Glucose + 6 ADP + 6 P_i + 4H⁺

Anabolism of Glucose - Regulation

Of course, some regulation needs to occur, otherwise you'd be breaking down glucose at the same time that you're producing it, which would be really counter-intuitive. For the most part, regulation is handled by the presence or absence of "ingredients" that are required for the process to occur.

Another thing that's worth mentioning is that most amino acids (basically all of them except for leucine and lysine) can upregulate gluconeogenesis. Glucogenic amino acids can enter the citric acid cycle at various points, causing an increase in oxaloacetate production. An increase in oxaloacetate production then causes an increase in gluconeogenesis.

Anabolism of Fatty Acids - Reactions

Acetyl CoA serves as the main "building block" for fatty acids. Excess acetyl CoA can be diverted from the citric acid cycle in order to store energy. The first step of this process is the transport of acetyl CoA from the mitochondria into the cytosol, where fatty acid synthesis occurs.

Acetyl CoA can't exit the mitochondrial matrix as it is. Instead, it has to combine with oxaloacetate to form citrate (which you might remember as being one of the steps of the citric acid cycle), which can then exit the mitochondria through the citrate/pyruvate shuttle. Once in the cytosol, ATP-citrate lyase can break citrate back down into oxaloacetate and acetyl CoA.

The next step now is to convert acetyl CoA into malonyl CoA. This is a carboxylation reaction (i.e. a reaction in which a carboxyl group is added). This requires acetyl CoA carboxylase and some ATP. After this happens, the building happens, catalysed by fatty acid synthase. Fatty acid synthase is a multi-enzyme polypeptide, which basically means that it's a one-stop shop of all of the enzymes that you need for making a new fatty acid. The growing fatty acid chain is continually bound to the enzyme, so side reactions are reduced.

There are many steps involved, but given that we didn't go into a massive amount of depth, I don't think we need to know what attacks what and all those nitty-gritty details. We might need to know the overall reaction though:

Acetyl CoA + Malonyl CoA + 14NADPH + 14H⁺ --> Palmitate + 7CO2 + 14NADP⁺ + 8CoASH + 6H₂O

Note that NADPH is required in this process. ATP is also required to synthesise malonyl CoA in the first place, according to the following reaction:

Acetyl CoA + ATP + HCO₃^- --> Malonyl CoA + ADP + H₂O

Anabolism of Fatty Acids - Regulation

There are two main sites of fatty acid synthesis: conversion of acetyl CoA to malonyl CoA, and transport of already-formed fatty acids into the mitochondria.

Let's start with the first site: formation of malonyl CoA. Regulation of this step is quite simple: having an excess of citrate, which leads to an excess of acetyl CoA, will upregulate formation of malonyl CoA (I guess the cell wants to get rid of its excess acetyl CoA?). Conversely, an excess of palmitic acid, or fatty acids in general, can provide negative feedback, preventing further formation of malonyl CoA.

Now for the second site of regulation: transport of fatty acids into the mitochondria. If transport into the mitochondria decreases, fatty acids can build up in the cytosol, negatively regulating formation of malonyl CoA, as I just described.

Explain the difference between glycolysis, glycogenolysis, gluconeogenesis and glycogenesis

• Glycolysis: Breakdown of glucose to release energy.
• Glycogenolysis: Breakdown of glycogen to form glucose.
• Gluconeogenesis: Formation of glucose from a source other than glycogen.
• Glycogenesis: Formation of glycogen from glucose.

Remember: -lysis = breakdown, -genesis = formation.

Have an understanding of the energy demands of anabolic processes.

I'm not really sure what to put here other than that anabolic processes tend to require energy, which is usually generated by catabolic processes.

Respiratory Diseases

First post for PHYL3002 after the study break! This post will touch on a lot of topics that I've spoken about before.

Types of Lung Disease

Lung diseases can be classified into several different categories: infections, tumours, chronic and pulmonary vascular diseases. For this post, we will be mainly looking at chronic lung diseases, like asthma and COPD.

There are also several other types of respiratory disease that don't necessarily involve the lung. For example, haematological disorders such as anaemia can reduce the oxygen-carrying capacity of the blood. Neuromuscular diseases can also impact the diaphragm and other muscles involved in breathing.

Back to chronic lung diseases! Chronic lung diseases can be broken down into two main categories: restrictive disease (in which compliance is reduced and changes in lung volume are reduced) and obstructive disease (in which resistance is increased and flow rate is reduced). Obstructive disease can then be broken down into reversible (i.e. responds well to bronchodilators) and non-reversible. An example of a restrictive disease is pulmonary fibrosis, an example of a reversible obstructive disease is asthma and an example of non-reversible obstructive disease is COPD. (I'll go into all of these in more detail).

Lung Function Tests

As mentioned above, restrictive diseases are marked by reduced compliance and obstructive diseases are marked by increased resistance. To directly measure compliance, you need to know intrapleural pressure, whereas to directly measure resistance, you need to know alveolar pressure. Unfortunately, these parameters are difficult to measure. Plethysmography, which uses a "body box," can measure these, but plethysmographs are expensive and not commonly found. Hence, we have to use other measures to help us monitor these diseases.

Firstly, we can use spirometry to measure different volumes. I've explained spirometry and the values that it can measure here. I've also described the pattern of lung volume changes in obstructive vs. restrictive diseases here.

Spirometry can't measure all lung volumes- we need to use the helium dilution technique to measure functional residual capacity (and by extension residual volume and total lung capacity), as explained here. Sometimes a little bit of CO is used at the same time in order to determine the diffusion capacity of the lung. This is because CO has similar diffusion properties to O₂. (The amount of CO used is obviously low so we don't kill the patient while we're at it.) This gives us a value called D_LCO, or the CO diffusion capacity of the lung.

Commonly used indices for resistance include PEF (peak expiratory flow), FEV₁, FEV₁/FVC ratio and flow-volume loops. I've discussed PEF and flow-volume loops, as well as how they change in disease states, here. FEV₁ was discussed here.

Blood gases can also be tested in order to test lung function. pH, arteriolar O₂ and CO₂ can all be measured. These measurements can also be used to calculate AaDO₂, or the alveolar-arterial oxygen difference.

Yet another test that can be done is the nitrogen washout test. This tests whether or not the alveoli have filled up relatively evenly. In the nitrogen washout test, the patient inspires 100% oxygen and then exhales. Normally, the graph of expired N₂ will start pretty flat, as the alveolar dead space will still be filled with the 100% oxygen that was just inhaled. As exhalation continues, though, the expired N₂ will increase. Eventually, when the alveoli are reached, a plateau phase will be reached in which the exhaled N₂ remains constant for a bit. If there is non-uniform ventilation, however (i.e. the alveoli do not fill up evenly), there will be no plateau phase: instead the expired N₂ will increase steadily.

Examples of Lung Diseases

Asthma

See previous post: The Respiratory System

Asthma is a reversible obstructive disease marked by airway wall thickening, smooth muscle thickening, mucus production and infiltration by inflammatory cells, such as eosinophils. As mentioned above, it is considered to be reversible because it can be helped by bronchodilators.

Bronchitis

See previous posts: COPD and Respiratory Pathophysiology 1

Another thing to be aware of is that broncholitic asthma is a type of chronic bronchitis that can see some improvements via a bronchodilator. It is possible, however, that broncholitic asthma is simply chronic bronchitis and asthma together in the same person.

Emphysema

See previous posts: COPD and Respiratory Pathophysiology 1

COPD

COPD is basically an umbrella term that covers bronchitis and emphysema. Both can cause fun stuff like obstruction, V'/Q' mismatch, pulmonary hypertension and right heart failure.

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis, in contrast to the diseases covered above, is a restrictive disease. As the name suggests, it is the formation of scar tissue (fibrosis) in the lung for no apparent reason ("idiopathic" is a fancy term for saying "we don't know"). While many lung volumes, like TLC, FRC, RV and FVC can fall, FEV₁/FVC ratio is often increased in this group (due to a normal FEV₁ and reduced FVC).

Excitation-Contraction Coupling in Skeletal Muscle

In a previous post, I covered excitation-contraction coupling in smooth muscle. In this post, I'll be covering excitation-contraction coupling in skeletal muscle. Unfortunately there's no nice little summary for this one, so I guess I'll have to figure out what's important :/

Excitation-Contraction Coupling

There are three main steps in the excitation-contraction coupling of skeletal muscle:

1. The action potential travels along the surface of the sarcolemma and down the transverse-tubular (T-tubular) system
2. Depolarisation activates voltage sensors (a.k.a. dihydropyridine receptors or L-type calcium channels).
3. Activation of voltage sensors opens ryanodine receptors on the sarcoplasmic reticulum (SR) membrane.

Now let's go over each step in turn!

Step 1: Action potential

The action potential works in pretty much the same way it does in most other cells: sodium influx causes the cell to depolarise and potassium efflux causes the cell to repolarise. Nothing too interesting here. The cell structures involved, however, are a bit different: the sarcolemma (muscle cell membrane) actually folds into the cell as well, creating T-tubules (transverse tubules). The action potential can travel down these T-tubules.

Step 2: Activation of voltage sensors 

As mentioned above, the voltage sensors involved are also called dihydropyridine receptors (DHP receptors, or DHPR), or L-type calcium channels. These receptors are located in the T-tubules in tetrad formations (i.e. they appear in groups of 4). They're called dihydropyridine receptors because they can be blocked by dihydropyridines, and they're called L-type calcium channels because, guess what, they let calcium through. Well, some of them do, which leads me to my next point.

Only around 5% of dihydropyridine receptors actually allow calcium through, and in fact extracellular calcium is not required for contraction, at least not in the short term. The extracellular calcium coming through these channels mainly just counteracts the calcium that is pumped out of the cell. That's not to say that they're not important: in fact, DHP receptors are critically important for contraction. It's been found that dysgenic myotubes, which have no DHP receptors, are unable to contract. How does this work, given that they're calcium channels and extracellular calcium has little effect on contraction? The answer to that question involves another function of these channels, which I'm about to introduce you to...

Step 3: Activation of ryanodine receptors (RyR)

Parts of the sarcoplasmic reticulum (SR) of skeletal muscle cells are located right next to the T-tubules. The SR has ryanodine receptors (also mentioned here and here), which are located close to the DHP receptors on the T-tubule. This allows RyRs and DHPRs to become mechanically linked, so that when DHPRs are activated, RyRs are activated too.

Let's take a closer look at the ryanodine receptor. Ryanodine receptors are made up of four monomers. They have a central channel with four side channels that branch off, and essentially release the calcium sideways (if they released calcium straight ahead, then the calcium would just bump straight into a DHPR). There are more RyRs than DHPRs- roughly every second RyR faces a DHPR.

RyRs can be stimulated by ATP and Ca²⁺. ATP is almost always bound to RyRs, unless there is a severe ATP shortage. Despite this, RyRs are usually under inhibitory control by Mg²⁺. When the DHPR is activated, certain parts (particularly the II-III loop of the α₁ subunit) interact with the RyR. This decreases the affinity of the RyR to Mg²⁺, causing release of Mg²⁺ and activation of the RyR.

When the RyR is activated, calcium can leave the SR. This calcium can then trigger contraction, as described here.

Modulation of Contraction

Contraction is not an all-or-nothing event. There are several different ways in which force can be modulated. Ca²⁺ sensitisation refers to an increased force for the same amount of Ca²⁺ (and Ca²⁺ desensitisation just has the opposite meaning). Ca²⁺ sensitisation can be modulated by temperature, pH and myosin light chain kinase. (Note: while MLCK activation was required for smooth muscle contraction, it's not required for skeletal muscle. MLCK activation simply improves the muscle's ability to contract.)

There are two main ways in which Ca²⁺ sensitisation may take place. Firstly, when the muscle is stretched, the myofilament is compressed, pushing thick and thin filaments closer together. This increases the binding probability, which in turn increases formation of crossbridges, crossbridge cycling and so on. Secondly, when MLCK is activated and able to phosphorylate the regulatory light chain, the myosin head can move closer to the actin filament, also increasing the binding probability and whatnot.

Cessation of contraction

Just like in other types of muscle, SERCA is around to pump Ca²⁺ back into the sarcoplasmic reticulum. SERCA is most highly concentrated in the longitudinal tubules, which are tubes of SR that run along the muscle fibre.

Calsequestrin, which I'm fairly sure I've spoken about before but can't find the post in which I mentioned it, is a calcium-binding protein found in the SR. Calcium binding to calsequestrin reduces the concentration of free calcium in the SR, which makes it easier for SERCA to keep pumping calcium in.

Ca²⁺-calsequestrin complexes can also associate with another protein called triadin. This Ca²⁺/calsequestrin/triadin complex can increase the opening probability of the RyR.

Beta-Oxidation

So, did you, like me, think that you could forget everything that you learned in first year about β-oxidation? Well, think again!

Describe the reactions in, regulation of and cellular location of beta-oxidation.

Beta-oxidation, which is the breakdown of fatty acids to form acetyl-CoA, has three stages. In the first stage, fatty acids in the cytosol are activated. In the next stage, they are transported into the mitochondria. In the third and final stage, the actual β-oxidation process occurs, breaking down the acyl chains to form acetyl CoA, which can then enter the citric acid cycle.

First stage: Activation

In the activation state, ATP reacts with the fatty acid to form an acyl-adenylate intermediate and pyrophosphate. The acyl-adenylate intermediate reacts with acetyl-CoA to form a tetrahedral intermediate which breaks apart into fatty acyl-CoA and AMP. This reaction is catalysed by acyl-CoA synthetase, and can be summarised as follows:

Fatty acid + CoASH (i.e. acetyl-CoA) + ATP -> Fatty acyl-CoA + AMP + pyrophosphate

Second stage: Transport

Since the mitochondrial membrane is tough to cross, there is a convoluted transport system in place that involves carnitine transporters (CPTI and CPTII). CPTI, located on the outer mitochondrial membrane, reacts fatty acyl-CoA in the cytosol with carnitine in the space between membranes to form CoASH in the cytosol and acylcarnitine between the membranes. Acylcarnitine then passes through a translocase to CPTII, which is located in the inner mitochondrial membrane. Here, it combines with CoASH from the mitochondrial matrix. This produces carnitine, which is released back into the space between membranes (essentially recycling it) and acyl-CoA in the mitochondrial matrix.

Third stage: β-oxidation

The process of β-oxidation itself consists of four steps, which can be summarised as oxidation, hydration, oxidation and cleavage:

1. Oxidation of the fatty acyl-CoA to trans-Δ²-enoyl-CoA via acyl-CoA dehydrogenase. Produces FADH₂.
2. Hydration of trans-Δ²-enoyl-CoA to 3-L-hydroxyacyl-CoA via enoyl-CoA hydratase.
3. Oxidation of 3-L-hydroxyacyl-CoA to β-ketoacyl-CoA via 3-L-hydroxylacyl-CoA dehydrogenase. Produces NADH.
4. Cleavage of β-ketoacyl-CoA to a shorter fatty acyl-CoA and acetyl-CoA via β-ketoacyl-CoA thiolase.

Each round of β-oxidation produces one acetyl-CoA molecule (which can go on to produce 12 ATP), 1 FADH₂ (= 2 x ATP) and 1 NADH (= 3 x ATP). (The exception is the last round, as that produces two acetyl-CoA molecules, along with 1 FADH₂ and 1 NADH.) As fatty acid chains are quite long, this cycle will proceed several times, producing quite a lot of ATP per fatty acid chain. Remember that you need to subtract 2 x ATP to get the overall yield, as 2 ATP molecules were consumed in the activation step.

β-oxidation is not the only process available for the breakdown of fatty acids. There are other minor pathways that can help with the breakdown of fatty acids with an odd number of carbon atoms, unsaturated fatty acids, fatty acids with methyl groups and so on.

Explain why ketone bodies are important and how they are formed.

Ketone bodies are a lipid-based yet water-soluble energy source. They are more commonly used by the skeletal and cardiac muscles, but can also be used by the CNS in cases of starvation. The main ketone bodies are β-hydroxybutyrate and acetoacetate. Most ketone bodies are formed in the liver.

There are several steps in the formation of ketone bodies:

1. Formation of acetoacetyl-CoA from acetyl-CoA via thiolase
2. Formation of HMG-CoA via HMG-CoA synthase (requires another acetyl-CoA as a cofactor)
3. Formation of acetoacetate via HMG-CoA lyase
4. Formation of β-hydroxybutyrate (requires NADH).

Ketone bodies can also be converted back into acetyl-CoA:

1. β-hydroxybutyrate converted into acetoacetate via β-hydroxybutyrate dehydrogenase (restores NADH)
2. Acetoacetate converted into acetoacetyl-CoA via β-ketoacyl-CoA transferase
3. Acetoacetyl-CoA converted into acetyl-CoA via thiolase

Have an understanding of the nomenclature of the common fatty acids.

See earlier post: Chemistry of Fatty Acids and Lipids

Appreciate the metabolic changes resulting from starvation.

See earlier post: Weight Loss and Exercise. Remember, glycogen is preferentially used first in a fasting stage. However, glycogen gets used up after around 24 hours, whereas fatty acids can be stored for weeks.

CO2 Transport and Acid/Base Balance

Discuss CO₂ transport in blood

See earlier post: Composition of the Blood

Describe the CO₂ dissociation curve

CO₂, just like O₂, can bind to haemoglobin. It binds to a different part of haemoglobin (the amino group as opposed to the haem group), but O₂ and CO₂ both cause structural conformations such that the two can't bind at the same time. In fact, there's a name for this: the Haldane Effect refers to increased binding of CO₂ when less O₂ is bound.

The CO₂ dissociation curve has a very different shape to the O₂ dissociation curve. As you should know, the O₂ dissociation curve is sigmoidal: it has a steeper part and a plateau phase. The CO₂ curve, however, is just a simple curve, like the slope of a hill. In fact, when you get within the range of CO₂ concentrations that you would normally see, the slope is pretty much linear.

Over normal ranges, the CO₂ dissociation curve is steeper than that of the O₂ dissociation curve. This is because the CO₂ dissociation curve lacks a plateau phase.

Discuss the link between CO₂ and pH

Increased CO₂ causes H⁺ concentration to increase (which means that pH decreases), due to the buffer system mentioned here. Decreasing CO₂ has the opposite effect: the pH will increase.

The pH change can be quantified by using the Henderson-Hasselbalch Equation, which you might remember from CHEM1004 (assuming that you haven't shut the pain out of your mind). As you may (or may not) remember, the Henderson-Hasselbalch equation is pH = pKa + log([A^-]/[HA]). We will now apply this equation to the bicarbonate buffer, which I mentioned here and will mention again later on in this post. The pKa of this buffer is 6.1, allowing us to make the following substitution:

pH = 6.1 + log([HCO₃^-]/[CO₂])

The issue with using this formula as it is is that we usually don't measure the concentration of carbon dioxide, but rather the partial pressure of carbon dioxide. Not to worry, however, as Henry's Law tells us that [CO₂] = 0.03 * P_CO2. We can then make this substitution:

pH = 6.1 + log([HCO₃^-]/(0.03*P_CO2))

Understand the importance of acid-base homeostasis in the body

Acid-base homeostasis is important because if your blood gets too acidic, you die, and if your blood gets too alkaline, you die. So please ignore any quack that tells you to make your blood more alkaline.

Discuss the regulatory systems contributing to acid-base homeostasis

The main regulatory systems are buffers in the blood, the respiratory system and the renal system.

Buffers

The main pH buffering system of the blood is the bicarbonate system, which I mentioned here. Phosphates (HPO₄^2- and H₂PO₄^-) can also serve as buffers. Proteins can also serve as a buffer, as detailed here. Proteins have a high buffering capacity, but are slow to respond.

Respiratory System

The respiratory system controls pH by regulating the concentration of CO₂. This can take a few minutes to hours to kick in.

Renal System

The renal system takes longer (hours-days) to regulate pH. It mainly regulates the concentration of HCO₃^- via affecting its reabsorption or producing more of it in renal tubule cells. The renal system can also increase the secretion of H⁺. The problem with the latter, however, is that less K⁺ can be secreted when this happens, causing an increase in serum K⁺ concentrations, leading to hyperkalemia. This causes a range of problems in the cardiovascular, neuromuscular and gastrointestinal systems. HCO₃^- reabsorption is described in more detail here.

Discuss the Davenport diagram

Ew, diagrams. Diagrams = drawing, and drawing = effort. Oh well then, if I must...

The Davenport diagram has three main features: pH on the x-axis, plasma bicarbonate on the y-axis and a set of curved lines called isocapnia lines. Each isocapnia line represents a different partial pressure of carbon dioxide. Higher isocapnia lines represent higher partial pressures of carbon dioxide.

I've also drawn a whole bunch of random dots on the diagram. Well, they're not totally random, though now looking at it I've decided that I haven't used the best lettering system. Oh well.

Let's start from point D, which is pretty much in the middle. Let's pretend for now that point D is the normal state of bicarbonate concentration, carbon dioxide pressure and pH.

In respiratory acidosis, represented by point A on the graph, CO₂ increases and pH decreases. Respiratory acidosis may be due to hypoventilation (too little breathing), which causes a buildup of CO₂. This hypoventilation, in turn, may be due to damage to the respiratory centres or some kind of obstruction. The kidneys can compensate for this by increasing bicarbonate, leading us to point B, where the pH is back to normal.

In respiratory alkalosis, represented by point G on the graph, CO₂ decreases and pH increases. This is usually due to hyperventilation, which can occur due to the effects of drugs, CNS disorders and so on. The kidneys can compensate by getting rid of bicarbonate, leading us to point F.

In metabolic acidosis, too little bicarbonate is available, causing pH to drop from point D to point C. This may be due to alcohol abuse, diabetes, lactic acidosis, salicylate (aspirin) poisoning or renal tubular dysfunction. This can be compensated for by blowing off more carbon dioxide, leading us to point F.

In metabolic alkalosis, too much bicarbonate is available, causing pH to rise from point D to point E. This may be due to vomiting, hyperaldosteronism or exogenous steroids. This can be compensated for by blowing off less carbon dioxide, restoring pH to point B.

COPD

I've already written quite a bit on COPD here, here and here, but there's still a little bit more that I haven't said yet, so bear with me!

Also, there's no nice summary that might help me pin down what hasn't been covered before. Me no like.

Defence Mechanisms

The lung has several defence mechanisms to prevent bad stuff from happening. Nasal hair and mucus serve as physical barriers. The respiratory tract also has immune system cells, immunoglobulins and so forth. If part of the lung is damaged, neighbouring progenitor cells can divide and differentiate to replace them, but if large parts of the lung are damaged, scarring can result. Cells that may divide and replace dead cells include basal cells in the bronchioles, Clara cells further down, and type II alveolar cells (which can replace type I alveolar cells).

Chronic Bronchitis and Emphysema

The two main types of COPD are chronic bronchitis and emphysema. They are quite distinct, but are grouped together for historical reasons.

Chronic Bronchitis

Chronic bronchitis is defined as sputum production for most days for 3 consecutive months for 2 consecutive years.

Chronic bronchitis can be caused by smoking. Cigarette smoke can activate macrophages and neutrophils, which in turn can activate proteases and oxidants, which can cause a lot of damage. Oxidative stress may upregulate goblet cells, leading to mucus hypersecretion.

Emphysema

Emphysema is defined as distal air-space enlargement of the terminal bronchioles due to the alveolar walls breaking down, as explained here.

Emphysema can also be caused by smoking. As mentioned above, cigarette smoke ultimately causes the release of many proteases and oxidants. Additionally, epithelial cells can be harmed, leading to fibrosis.

Diagnosis

Diagnosis of COPD can be done via tests of FEV1, such as flow-volume plots and spirometry. COPD does have many different phenotypes, however, so sometimes many different indices are used in order to more specifically define a particular patient's brand of COPD.

Prognosis

Not all patients with COPD decline. Genetic factors may affect the progression of the disease. Predictive factors include age, BMI and number of previous hospitalisations.

Electron Transport Chain and Oxidative Phosphorylation

Know the processes of ETC and oxidative phosphorylation

See earlier post: Cell Biology- Introduction and Energy Production

Another thing worth mentioning is that the transport of electrons goes down an energy gradient: electrons move from a higher energy state to a lower energy state.

Regular aerobic exercise training can increase our mitochondrial volume and electron transport chain components, making the oxidative phosphorylation process more efficient.

Also, it's always fun to learn about what can go wrong :P Leigh's Disease, also known as Subacute Necrotising Encephalomyopathy, is caused by dysfunctions in the complexes in the electron transport chain and/or mutations in the ATP synthase. Cyanide poisoning occurs when cyanide binds to Fe³⁺ in the haem of cytochrome oxidase (complex IV), preventing electrons from being passed further along. This creates a "backup" of electrons, which ultimately ceases the transport of protons. This stops ATP from forming, eventually causing death.

Describe the alternate pathway of anaerobic metabolism

When oxygen isn't available, it can't accept electrons at the end of the electron transport chain. This causes a backup of NADH. As mentioned here, NADH can inhibit the phosphorylation and activation of pyruvate dehydrogenase. Inhibition of pyruvate dehydrogenase causes pyruvate to accumulate and eventually get turned into lactate in animals or plants, or ethanol in yeast.

In animals and plants, lactate/lactic acid is formed. Lactate dehydrogenase breaks down pyruvate into lactate, converting NADH to NAD⁺ as it does so. Eventually, lactic acid does need to be metabolised, but this metabolism requires oxygen, leading to an "oxygen debt."

In yeast, as well as in some plants, ethanol can be formed. Firstly, pyruvate is converted into acetaldehyde, releasing carbon dioxide. Alcohol dehydrogenase can then break down acetaldehyde into ethanol, converting NADH to NAD⁺ as it does so.

Also, as you should probably know, not too much ATP can be produced if pyruvate can't enter the citric acid cycle and undergo oxidative phosphorylation (only 2ATP per molecule of glucose can be produced in anaerobic metabolism, whereas 38ATP can be produced in aerobic metabolism).

Explain the purpose of generating lactate

When lactate is generated, NADH is recycled to NAD⁺. This allows it to be reused in further glycolysis.

Describe the Cori cycle & explain its role

The Cori cycle recycles lactate back to glucose. Lactate is co-transported out of cells of the body, along with H⁺. It can then enter the liver, where lactate dehydrogenase restores it to pyruvate. (Yup, lactate dehydrogenase again. I just sent an email asking my lecturer how lactate dehydrogenase can modulate the conversion of pyruvate into lactate AND the conversion of lactate into pyruvate.) Pyruvate can then be converted to glucose in the process of gluconeogenesis (i.e. producing glucose from sources that aren't glycogen).

Explain why different parts of the metabolic pathways occur in different cell types

Different parts of the metabolic pathways occur in different cell types due to different expression of proteins, enzymes and so on. I'm guessing that blood supply may also play a role.

Gas Exchange and V'/Q' Ratio

I can't be bothered thinking up an introduction for this post, so let's just get into it!

Recall the blood pressures in the pulmonary circulation.

Blood pressures in the pulmonary circulation are lower than those in the systemic circulation. The pressure in the pulmonary arteries is around 22/8. The capillary pressure is also around 10mmHg less than in the systemic capillaries.

Explain how the Starling equilibrium is altered in pulmonary capillaries.

Firstly, you might want to refresh your memory on the Starling equilibrium by looking here. In pulmonary capillaries, one of the outward driving pressures (blood pressure) is greatly reduced as compared to the systemic circulation. How, then, is this compensated for?

Alveoli affect the Starling equilibrium as well. Air pressure within the alveoli pushes outwards (i.e. towards the blood), whereas the surface tension pulls stuff inwards (i.e. out of the blood). Everything's usually all nicely balanced so that pulmonary oedema (fluid in the lungs) doesn't occur (though obviously this can change in disease states).

Define V'/Q' mismatch

First some quick definitions: V' (which is sometimes displayed as V with a dot on top) is airflow, whereas Q' (again, Q with a dot on top) is blood flow. Blood flow and airflow are not uniform throughout the lung- some areas have better blood flow than airflow, and some areas have the opposite problem. For optimal gas exchange, blood flow should equal airflow, but this isn't possible everywhere in the lung. All of this can be expressed as the Ventilation-Perfusion ratio, or V'_A/Q'.

Now I'll give a quick overview on the main factors controlling pulmonary blood vessel resistance and air pressure (both of which ultimately control flow, as flow is equal to (change in pressure)/resistance):

For blood flow, we need to look at how many pulmonary vessels are open or closed. At rest, many vessels are closed. When blood pressure increases, more blood vessels are open, and those that are open may distend. This causes a reduction in pulmonary resistance. When blood pressure decreases, more vessels close off, increasing pulmonary resistance.

For air flow, see my earlier post: Mechanics of Breathing. In particular, read the part about compliance and the LaPlace equation.

Explain how V'/Q' mismatch produces hypoxia

As I just mentioned, airflow and blood flow are not equal everywhere in the lung. To understand the consequences of this, let's consider the two gases separately.

Oxygen

In underventilated alveoli (i.e. alveoli with more blood flow than airflow), the blood will arrive and leave with a smaller than usual increase in O₂ due to the limited amount of airflow. In overventilated alveoli (i.e. alveoli with more airflow), there will be a larger than usual increase in O₂.

However, these do not cancel each other out! Remember, haemoglobin saturation plays a large role in oxygen content of the blood. When blood flow and air flow are well-matched, you'll get a normal increase in airflow, and haemoglobin saturation will go back up to 95-100% (after becoming unsaturated during oxygen transfer to the cells of the body). When there is a larger than usual increase in O₂, haemoglobin saturation won't change much (as you can't get more than 100% haemoglobin saturation), so you're really not changing the oxygen concentration much at all! Hence, V'/Q' mismatch produces hypoxia.

Carbon Dioxide

Carbon dioxide is the opposite to oxygen: underventilated alveoli will not remove as much CO₂ as an over-ventilated one. These do, however, cancel out, as saturation is not an issue here. Hence, V'/Q' mismatch will produce little (if any) hypercapnia.

V'/Q' mismatch is a very common cause of hypoxia in disease states. V'/Q' mismatch is particularly marked in disease states such as asthma, where air will flow into healthy alveoli, whereas blood will flow to affected alveoli.

Describe the cause of orthostatic V'/Q' mismatch

When we are standing, airflow goes to the bottom of the lung. This is because gravity causes alveoli to stretch and become less compliant, particularly those towards the top (apex) of the lung. Blood flow also goes to the bottom of the lung when we're standing, as the higher blood pressure at the base causes vasodilation (as explained above). That sounds great, right? Airflow and blood flow increase in the same places!

Not quite. It's true that gravity does have an effect on both blood flow and ventilation, but it has more of an effect on blood flow than on ventilation. Hence, there is still some V'/Q' mismatch in most places in the lung. Towards the base of the lung, there will be more perfusion than ventilation; towards the apex, there will be more ventilation than perfusion. Ventilation and perfusion are relatively even at around the third rib.

Explain how V'/Q' mismatch is minimized in the normal lung 

In this post, I described how local metabolites can affect vasoconstriction and vasodilation. I also mentioned that O₂ is a vasoconstrictor everywhere except for in the pulmonary circulation, where it is a vasodilator. Well, that's relevant again: well-ventilated alveoli will cause vasodilation, whereas poorly perfused alveoli are hypoxic and cause vasoconstriction. In severe hypoxia, all of the pulmonary vessels can constrict, increasing blood pressure in the pulmonary circulation. This causes pulmonary hypertension, which can lead to oedema, right heart failure and death.

At really low levels of CO₂ (like really low), the airways may constrict to prevent more CO₂ from leaving. This generally isn't very important, however: most of our V'/Q' mismatch compensation is done by the blood vessels, rather than by the airways.

Toxicology of the Lung: Environmental and Occupational Hazards

I was really distracted during this lecture for some reason. Hopefully I can write about it though :P

Be able to identify the major anatomical zones of the human lung and describe the prevailing cell types within each region.

The major anatomical zones for our purposes here are the upper respiratory tract (also known as the extrathoracic region), the lower respiratory tract (bronchial region) and alveolar region.

There are over 40 cell types in the lung, but thankfully we don't need to know about all of them. I'll just provide a quick overview of some of the cells that you will need to know.

The epithelium of the trachea and bronchi have mainly ciliated cells (which push mucus around), as well as "Clara-like cells" (a.k.a. bronchiolar secretoglobin cells (BSCs)). The latter cells express CYP450, which, as you should know from last year, metabolise a lot of drugs.

Small bronchi and bronchioles express the same cells, though Clara cells are more prevalent than ciliated cells in this region.

Alveoli have two main cell types: AEC I (alveolar epithelial type I cells) and AEC II. AEC I are thin, squamous looking cells that allow for gas exchange. AEC II are secretory cells that produce surfactants to lubricate the lung.

As mentioned above, Clara cells have CYP450. AEC II cells also have high levels of this enzyme. Some isoforms, such as CYP1A1, may be higher in smokers. CYP levels in the lung are, as you have probably guessed, nowhere near as high as in the liver (lung CYP is only around 10-30% of that in the liver). There are also plenty of other enzymes that can metabolise drugs.

Identify several factors that influence chemically‐induced pulmonary injury, including the role of metabolism, timing and duration of exposure, and the route of entry.

• Metabolism: As mentioned in an earlier post, some toxic compounds require bioactivation before producing their toxic effects, whereas others are dangerous right from the start.
• Route of entry: Some toxic compounds enter directly into the lung via inhalation. Others enter the body in different areas but end up affecting the lung anyway.
• Timing: Toxicity can be acute or chronic.
• Duration: Self-explanatory really...

One of the difficulties with toxicology is trying to figure out how much a person has been exposed to. In fact, there's a whole field called dosimetry which attempts to figure out ways to determine how much exposure an individual has had.

Identify chlorine and acrolein as major direct‐acting pulmonary toxicants, describing the main features of the oedematous acute lung injury accompanying intoxication with each agent, as well as basic aspects underlying their toxic actions.

Direct-acting pulmonary toxicants may cause damage by being electrophilic or by possessing extreme physicochemical properties. The two direct-acting toxicants covered in this lecture are chlorine (known for its role in WWI) and acrolein (mentioned earlier as a constituent of tobacco smoke).

Chlorine

Chlorine is a yellow-green gas that was used as a chemical weapon in World War I. Once inhaled, it can dissolve to form HCl and HOCl, which you should recognise as being bleaches. Neutrophils and macrophages are also activated, and neutrophil myeloperoxidase can produce even more HOCl. Furthermore, iNOS (inducible nitric oxide synthase) can produce NO, which can go on to form peroxynitrite (ONOO^-, which looks like "oh nooooo"). All of this can cause oedema, inflammation and so forth. The amount of gunk that gets generated in this process also clogs up the airways.

Throughout this process, reactive nitrogen species can react with tyrosine to form 3NT (3-nitrotyrosine). 3-NT can also serve as a marker of damage by reactive nitrogen species.

Acrolein

Acrolein, formed during the incomplete combustion of organic matter (including but not limited to tobacco, wood, plastics, polymers etc.), is highly electrophilic. This allows it to attack DNA, proteins and so on. Acrolein, unlike chlorine, has not been effectively used as a biological weapon due to its tendency to form polyacrolein chains which do not have these properties.

Acrolein is involved in a condition called Smoke Inhalation Injury (SII), which is, well, injury due to inhaling smoke. SII plays a major role in the morbidity and mortality of fire victims as it can cause pulmonary oedema. Interestingly enough, smoke produced from substances with low yields of acrolein tends to be less oedematogenic than smoke with higher yields of acrolein.

The events that take place in SII may be similar to those that take place in Acute Lung Injury (ALI). These events include activation of neutrophils and macrophages, which may increase production of free radicals and proteases. Additionally, blood vessels may become leakier due to damage, resulting in more fluid leaking out of the vessels, causing oedema.

Why is acrolein so bad? Acrolein is very reactive with many amino acids, allowing it to form a range of protein adducts (it's estimated that around 769 proteins can be adducted by acrolein). Many of these adducts contain a carbonyl group, allowing them to be trapped by certain reagents, such as biotin hydrazide. Acrolein adducts bound to biotin hydrazide can then be purified by using a column containing avidin, which binds to and traps biotin hydrazide. All of these trapped proteins can then be examined by using other techniques like agarose gel electrophoresis and mass spectometry.

Identify paraquat as an example of a major metabolism‐dependent pulmonary toxicant, showing appreciation for the factors underlying the vulnerability of the lung to this toxicant, and the role of free radicals in the onset of tissue injury.

Paraquat (PQ) is a herbicide that, if ingested, can injure the lung over 1-2 weeks by causing oedema, lesions and other fun things. It is metabolism-dependent, meaning that it needs to be metabolised before it can wreak havoc. PQ is metabolised in the lung (pulmonary bioactivation). (There is also extrapulmonary bioactivation, where a substance is bioactivated somewhere else. Cyclophosphamide is an example of one of these.)

If you manage to survive PQ poisoning, you're still not all clear: survivors of PQ poisoning are prone to Parkinson's disease. That's because paraquat is somewhat similar to MPTP which, as explained here, is toxic to dopaminergic neurons.

PQ readily builds up in the lungs because they can be taken up by polyamine transporters. Polyamines, as the name suggests, have multiple Ns in them. They play a role in a wide variety of events in the cell, from cell migration, mRNA stabilisation, chromatin function and so on. The distance between the Ns of paraquat is similar to the distance between the Ns of naturally-occurring polyamines, such as putrescine, spermidine and spermine, which makes it easy for the transporter to take up PQ.

So how does PQ do damage? When it is metabolised, it can form PQ free radicals. These PQ radicals can donate electrons to oxygen in order to form superoxide, which may combine with nitric oxide radicals to form ONOO^-, or peroxynitrite (yes, it's the oh no one again).

There are two main stages of PQ injury. In the first acute phase, or "destructive phase," AECs show swelling and disruption of organelles. In the second phase, or "proliferative phase," the alveolar space is filled with mononuclear profibroblasts, which become fibroblasts, leading to lung fibrosis.

A Review of Basic Muscle Physiology

Now we're onto skeletal muscle!

Gross and cellular structure of skeletal muscle

Muscle consists of muscle fibres (which are just muscle cells with a fancy name). Several muscle fibres wrapped in perimysium form a fascicle. Blood vessels run between fascicles.

Muscle fibres contain numerous myofibrils, which take up most of the space in the cell. The mitochondria, sarcoplasmic reticulum etc. just get squished up in between. The numerous nuclei are pushed to the outside of the cell.

Myofibrils are made up of thick and thin filaments, which form a banded appearance under a microscope. These produce contraction.

Structure and arrangement of the contractile filaments (the sarcomere)

Thin filaments consist of actin, tropomyosin and troponin. Actin makes up the bulk of the thin filament, tropomyosin covers the myosin binding sites on actin and troponin binds to and moves tropomyosin out of the way when it's time to allow contraction to take place.

Thick filaments in skeletal muscle are pretty much the same as those in smooth muscle (i.e. they are made up of myosin II). The tails of myosin filaments meet together in the middle of the thick filament, with the heads at either end. There is a small section in the middle that has only tails and is thus known as the "bare zone."

Thick and thin filaments are arranged in structures called sarcomeres. At either end of a sarcomere is a Z disc. Thin filaments bind to this Z disc and extend towards the centre of the sarcomere from either side. Thick filaments are located in the middle of the sarcomere, and are held in place by the M-line. There is some overlap between thick and thin filaments. The area containing the thick filament is called the A band, or "dark" band, as it looks dark under a microscope. The area containing only thin filaments (i.e. the bits where the thin filaments do not overlap the thick filaments) is called the I band, or "light" band. The area containing thick filaments only (i.e. no overlap with thin filaments) is also known as the H band.

There are other proteins within the sarcomere. Titin connects the M-line to the Z-line and is responsible for muscle elasticity. Nebulin wraps around actin and regulates its length.

How the contractile filaments interact to produce contraction (the sliding filament theory)

As I just mentioned above, the myosin heads are located at either end of the thick filament. These "heads" can bind to actin and pull it inwards over the myosin filament, causing contraction. This is known as the sliding filament theory (don't be fooled by the word "theory"- it's pretty well established). During contraction, the A band stays constant (as myosin doesn't change in length), but the I and H bands shorten due to increased overlap.

How skeletal muscle contraction is controlled

Contraction of skeletal muscle, just like in smooth muscle, requires cross-bridges to cycle. Cross-bridge cycling of skeletal muscle works pretty much the same way as smooth muscle. The main difference here is that the phosphorylation of the regulatory light chain is not the limiting step here: instead, it's tropomyosin.

As I mentioned earlier, tropomyosin can block the myosin binding sites of actin. When Ca²⁺ comes in, tropomyosin can be moved away from the myosin binding site, allowing binding and contraction to occur.

The effect of stimulation frequency of force output

When single action potentials are given, one at a time, the muscle produces a single twitch. When a few action potentials are given one after the other, a phenonemon called "twitch summation" occurs: subsequent twitches are larger than the first. (This isn't purely additive though: two action potentials won't create twice as much tension.) When a lot of action potentials are given, a large amount of tension is created for a long period of time (a state called "tetanus," which is the most well-known symptom of the disease with the same name).

Twitch summation occurs even though the amount of calcium influx is the same in all cases. To understand why this happens, we need to understand what happens when calcium is in the cell. Ca²⁺ can bind to troponin C, creating a Ca-Troponin C complex which is ultimately what moves the tropomyosin filament. The binding of calcium to troponin is relatively slow compared to the release. Hence, for a reasonable amount of Ca-Troponin complexes to form, calcium needs to be in the cell for a reasonable amount of time. If there are more action potentials, calcium can stay in the cell longer, forming more Ca-Troponin complexes. This results in more movement of tropomyosin away from the binding sites and thus more force generated.

The relationship between muscle length and force output

As you stretch a muscle, the basal force (minimum force produced) increases, but the active force (the difference between maximum and minimum force) decreases. This occurs for several reasons:

• At the optimal muscle length, all of the myosin heads are in close proximity with actin, allowing the maximum number of crossbridges to form. This produces the maximum amount of force.
• At longer muscle lengths, there is less overlap between myosin and actin filaments, so fewer crossbridges can form and less force can be produced.
• At very long muscle lengths, actin and myosin no longer overlap so no force can be produced.
• At shorter muscle lengths, actin filaments from either side get pushed over each other. This pushes the filament on one side closer to the myosin, and the filament on the other side further away from the myosin. When actin is pushed too far away from myosin, crossbridges cannot form, reducing the force.
• At very short muscle lengths, the myosin filaments run into the Z discs, preventing contraction from occurring at all.

The mechanisms responsible for graded contractions in skeletal muscle

When a muscle contracts, not all of it contracts at once. A single motor neuron will only activate a certain number of fibres. This set-up is known as a "motor unit." The amount of contraction generated by a muscle as a whole depends on how many motor units are activated. Usually, smaller motor units (i.e. motor neurons that only activate a small number of fibres) are activated first, allowing for fine control.

An Overview of Pharmaceutical Innovation

So our mid-semester for this unit is on Wednesday, and some of my friends kindly pointed out to me that this special lecture from the first week is likely to be examinable. The lecturer confirmed it as well. Guess I'll have to look over it then :P

This lecture is relatively short, but it doesn't come with a nice little lecture outline slide, so I'll have to actually make some decisions and decide what to include. Le sigh.

Drug Development

Drug development can be classified into three broad stages:

1. Discovery Phase- The phase in which the drug is "discovered." This starts by figuring out what you want to target and figuring out if the target is "druggable" (i.e. able to be targeted by a drug). Next up is the selection of a "lead compound" (that's the "lead" that rhymes with "bead", not the periodic table element) that might be able to bind to the drug, and then some optimisation to make it bind better or otherwise give it better pharmacokinetic properties. This gives you your "candidate drug."
2. Development Phase- The phase in which the drug is trialled and tested. This starts off with some preclinical development, in which some of the technicalities (like how to administer the drug) are sorted, and then the actual clinical trials and so forth.
3. Commercialisation Phase- The phase in which the drug is approved and commercialised, ready to make the drug companies some $$$.

Of course, in real life it isn't always that simple. In this post I'll cover three drugs that were discovered in different ways: omeprazole, paclitaxel and flecainide.

Omeprazole

Omeprazole treats gastro-oesophageal reflux disease (GORD), also known as GERD in North America (since they leave out the O in "oesophageal"). I've blogged about GORD/GERD here. As mentioned in that previous post, there are drugs to treat GORD. These include histamine receptor blockers (as histamine leads to acid production, as noted here) and proton pump inhibitors (PPIs). Omeprazole, produced by the UK company Astra, is one of the latter.

There were several obstacles in omeprazole development. The first test compounds that they used were not very efficacious. Also, another company managed to make some histamine blockers, filling the GORD treatment niche and putting pressure on Astra to come up with something different. Later on, however, Astra found another compound that was promising, but it was patented in Hungary, further halting development until the patent was found to have expired. This promising compound still wasn't what the company was looking for, as it had serious thyroid and vascular toxicity issues in the animal models that they tested. Eventually, however, promising human trials of omeprazole helped its development to come to fruition. In the early 1990s, omeprazole reached "blockbuster" status (i.e. it was a popular drug).

Paclitaxel

Paclitaxel is a drug that treats ovarian cancer. This lecture had a lot of random facts about ovarian cancer, and I doubt we have to remember them in that much detail, but here they are anyway. The categories of ovarian tumours include serous, mucinous, endometrioid, clear-cell, transitional and squamous cell, with serous being the most common. Ovarian cancer can also be subdivided into benign, intermediate and malignant.

Paclitaxel works by binding to β-tubulin. β-tubulin is an important component of microtubules, which form the spindles during cell division. Now, the slides don't say, and I didn't exactly take great notes from this lecture, but I'm guessing that that's how paclitaxel works: by inhibiting the spindles which would normally help a cell to divide. (This random abstract I found on PubMed seems to agree.)

Paclitaxel is derived from the Pacific Yew. Just like omeprazole, paclitaxel's development was also fraught with challenges. In the beginning, this compound wasn't seen to have much activity in tumour cell lines, so nobody really cared about it until President Nixon declared a "War on Cancer." It was then found that paclitaxel actually had an effect, but there was another problem: it was poorly soluble in water, and solubilising agents could be toxic. Eventually they figured out that they could solve this problem by using slow infusions. Yet another problem that paclitaxel development faced was a shortage of the Pacific Yew: it grows slowly and was endangered. Later on, however, chemists figured out how to produce it by using plant cells in vats, solving that issue.

Flecainide

Flecainide treats cardiac arrhythmias, which I've written about here. At first, dysrhythmic drugs had serious side effects. An example of this was procainamide, which had a very narrow therapeutic window. Flecainide is actually a fluorinated analogue of procainamide.

Once again, there were several challenges in flecainide development. For starters, they weren't really sure how it worked or what it targeted: they were mainly just testing it to see what would happen. Also, flecainide was slow to produce, which made the whole process slower. Eventually, though, flecainide was released as the first intentionally produced antidysrhythmic drug.

Smooth Muscle Response to Stretch

Last post on smooth muscle!

Explain how myogenic tone develops in vascular smooth muscle

As mentioned here, some smooth muscles, including those of the vascular system, contract in response to stretch. This process requires calcium to enter the cell from outside, and is thus blocked by nifedipine (a blocker of L-type calcium channels). But how exactly does this process work? Read on...

Describe the possible pathways for myogenic tone including the role of TRPC3,6, TRPM6, L-type channels, GPCR and autocrines.

Stretch-Gated Channels (SGCs)

There are many non-selective, stretch-activated channels in vascular smooth muscle. These are called stretch gated channels, or SGCs. The main ones include the epithelial sodium channel (ENaC), TRPC3, TRPC6 and TRPM4. Now, that's a lot of letters, so lets break it down. The TRP refers to the Transient Receptor Potential (TRP) family, the C or M refers to the family, and the number refers to the specific member of the family.

As there are a lot of different channels that might be involved, they can compensate for one another. Mice that lack the genes for TRPC6 appear to have upregulated TRPC3. This is probably why these mice still have the myogenic response.

G-Protein Coupled Receptors (GPCRs)

Now it's time to expand even more on the signalling pathways covered here and here! Yup, there's even more stuff that you're going to need to know. If you're not familiar with the signalling pathways that have already been covered, I suggest that you look back on these before proceeding or you're going to be lost in the alphabet soup to come.

Stretch can activate some G-protein coupled receptors, such as the AT₁ (angiotensin) receptor. Furthermore, some of the signalling molecules in the G-protein coupled receptor signalling pathway can increase the opening probabilities of the SGCs mentioned above. DAG (diacylglycerol) can bind to and increase the opening probability of TRPC3 and 6, whereas IP₃ does the same for TRPM4.

Autocrine and Paracrine Signalling Molecules

Smooth muscle can also release some mediators that can act in an autocrine (on the same cell) or paracrine (on neighbouring cells) fashion.

Phospholipase A (PLA₂) is a membrane-bound enzyme that is activated by stretch. When activated, it catalyses the formation of arachidonic acid, which can be further broken down to form 20-HETE and thromboxane A2 (TxA₂)- yup, the same TxA₂ mentioned in PHAR3303. These can diffuse out of the cell and bind to receptors (such as the G-protein receptors mentioned above) on the same cell or on neighbouring cells. Other signalling molecules that may act in this fashion include sphingosine-1-phosphate (S1P), UTP and ATP.

Describe DI induced bronchodilation and its relevance to asthma and COPD

DI = deep inhalation. When we take in a deep breath, it reduces bronchoconstriction. That's why it's so much easier to exhale after we take a deep breath in first. In patients with asthma or COPD, this mechanism may not work- a DI may cause no change, or maybe even bronchoconstriction.

Explain how length-adaptation and stretch induced dilation might be due to rearrangement of actin and myosin filament
Describe the labile nature of actin and myosin in smooth muscle

Smooth muscle is very adaptable. If you pin it out at a longer length, it will adapt so that that longer length becomes its new optimum length for contraction. If you pin it out at a shorter length, it will likewise adapt so that that shorter length becomes its new optimum length. Interestingly enough, no changes in calcium or myosin light chain phosphorylation are associated with this phenomenon, so something else must be at play.

That something else, believe it or not, is the ability of smooth muscle to add or remove contractile units (a property that is unique to smooth muscle). When smooth muscle contracts, it assembles its thick filaments (i.e. myosin filaments). This may seem counterintuitive, but when myosin is phosphorylated (as happens during contraction), it is more stable, which may help with polymerisation. Stretch triggers disassembly of these filaments so that they can reassemble at a new length. We're still not sure on all of the details, but the end result is that a muscle that is adapted to a shorter length will have fewer myosin filaments, whereas a muscle that is adapted to a longer length will have more myosin filaments.

Actin filaments are also important. Contraction triggers polymerisation of actin as well as myosin. Inhibiting the polymerisation of actin will also reduce the amount of force that can be produced.

Of course, it's not that simple in vivo. As loads on muscle are often oscillating (such as in airway muscle where you are breathing in and out all the time), the muscle may never be able to finish adapting to any length. This may be why airway smooth muscle often relaxes with oscillatory loads (such as the loads placed on it during regular tidal breathing).

There's also another phenomenon to take note of called shortening inhibition. Shortening inhibition basically means that the longer you leave a muscle contracted, the less able it is to contract.

Define Latch

Latch is a state in which the cross-bridges are attached, but are not cycling. We're still really not sure about how this happens, though: maybe the cross-bridges are dephosphorylated or something like that, preventing them from releasing, or maybe this is due to the polymerisation of actin filaments after contraction. In any case, the latch state is probably the reason why smooth muscle can maintain tone without using up a lot of ATP, despite smooth muscle contraction being less efficient than in other muscles (smooth muscle is consistently polymerising and depolymerising its filaments, and that shit takes energy).

The TCA Cycle

In my last post for BIOC3004, I wrote about glycolysis: the process in which glucose is broken down to pyruvate. That post did not cover the stuff that happens before and after this process: the breakdown of glycogen into glucose, and the entrance of pyruvate into the citric acid cycle.

Describe the reactions of the TCA cycle, where they occur within the cell and the regulation of the pathways.

From Glycolysis to Acetyl CoA formation

After glycolysis, which occurs in the cytosol, pyruvate enters the mitochondria where it is irreversibly converted to acetyl CoA with the help of pyruvate dehydrogenase, producing a little NADH along the way. Pyruvate dehydrogenase is actually a large complex made up of three subunits, each of which catalyses a single step in this reaction. Pyruvate dehydrogenase can exist in a phosphorylated (active) and dephosphorylated (less active) form. It is held in place by negative feedback mechanisms: when acetyl CoA, NADH and ATP levels increase, they can inhibit the phosphorylation of pyruvate dehydrogenase.

If pyruvate dehydrogenase is deficient, this can cause a condition called lactic acidosis, which may result in neurological defects and death. This is because pyruvate cannot become acetyl CoA, so it gets converted into lactate instead. Sometimes, this condition can be managed by eating fewer carbohydrates so that less pyruvate will build up.

The TCA Cycle

Enter long chain of reactions! All of these happen in the mitochondria.

1. Acetyl CoA and oxaloacetate (a four-carbon molecule) combine to form citrate. Requires citrate synthase.
2. Citrate forms isocitrate with the help of aconitase.
3. Isocitrate forms α-ketoglutarate with the help of isocitrate dehydrogenase. Forms NADH and CO₂.
4. α-ketoglutarate forms succinyl CoA with the help of α-ketoglutarate dehydrogenase. Also forms NADH and CO₂.
5. Succinyl-CoA forms succinate with the help of succinyl-CoA synthetase. Forms GTP.
6. Succinate forms fumarate with the help of succinate dehydrogenase. Forms FADH₂.
7. Fumarate forms malate with the help of fumarase.
8. Malate forms oxaloacetate with the help of malate dehydrogenase. Forms NADH.

Aaaand we're back to the beginning of the cycle!

It should be noted that this cycle is not strictly a cycle: some things can enter at different spots along the way, and some of the substances in the cycle can leave and do their own thing.

It should also be noted that NADH, FADH₂ and GTP don't come out of nowhere. NAD⁺, FAD and GDP are also required for the cycle, providing another mechanism through which the TCA cycle can be regulated.

Electrons carried by NADH and FADH₂ can then enter the electron transport chain in the inner mitochondrial membrane, but that's a subject for a later post.

Draw Pyruvate & Acetyl group of Acetyl CoA.

We have to draw these? I DID NOT SIGN UP FOR THIS SHIT >_>

Drew these on ChemDoodle, with a bit of wrestling with my computer. Enjoy.

Understand the energetics of aerobic metabolism.

Aerobic metabolism produces a net ATP yield of 38 molecules. You see, each molecule of NADH yields 3 ATP after going through the electron transport chain (which I'll talk about in a later post), whereas each molecule of FADH₂ forms 2 molecules of ATP. Hence you get the following:

• Glycolysis: 2 ATP + 2 NADH (x3 = 6ATP) = 8 ATP
• Pyruvate to acetyl CoA: 1 NADH (x3 = 6 ATP) = 3 ATP x 2 (because you get 2 molecules of pyruvate for every molecule of glucose) = 6 ATP
• TCA cycle: 3 NADH (x 3 = 9 ATP) + 1 FADH2 (x 2 = 2 ATP) + 1GTP (=1 ATP) = 12 ATP x 2 = 24 ATP
• 8 + 6 + 24 = total yield of 38 ATP

Know the pathway of glycogen breakdown.

Glycogen can be broken down to glucose in the process of glycogenolysis. I've covered this in more detail in an earlier post: Carbohydrates- Metabolism of Glycogen.

Toxicology of Tobacco II

In my last post, I wrote about the carcinogenic compounds in cigarettes. In this post, I'll be talking about free radicals.

Demonstrate basic understanding of the main chemical species formed during oxidative stress

Firstly, I should give a quick definition of oxidative stress. Oxidative stress occurs when there are more free radicals produced than removed. (Free radicals can be removed by antioxidants.)

The main species formed from oxidative stress can be classified into two main categories: reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS include superoxide, hydrogen peroxide and hydroxyl radicals. RNS includes NO radicals and ONO₂CO₂^-, which I know virtually nothing abut other than that it can be very damaging.

Show an understanding of how redox-cycling quinones are a source of superoxide radicals in tobacco smoke-exposed lungs.

Redox-cycling quinones in tar can produce free radicals, such as superoxide. Some quinone-containing compounds, such as the hydroquinone-quinine complex, are formed during the incomplete combustion of tobacco leaves.

Identify major products of oxidative damage to proteins and unsaturated fatty acids, and their use as biomarkers.

8-isoprostane is a common product of oxidative damage. It is formed by free radical attack on arachidonic acid. Carbonyl-adducted proteins (i.e. proteins with carbonyl attached) are also common products of oxidative damage. These products can also be used as biomarkers, i.e. their concentrations can be measured to determine the extent of oxidative stress,

Show how smoke-derived ROS may cause 2 pathological features of COPD: elastase activation and proinflammatory gene expression secondary to chromatin remodelling.

Elastase Activation

Human neutrophil elastase (HNE) mediates degradation of elastin fibres in alveolar walls, leading to emphysema. Usually, HNE is inhibited by α₁-antitrypsin, but when α₁-antitrypsin is oxidised due to ROS, it can no longer bind to and inhibit elastase.

Gene Expression

ROS may regulate kinases that affect the acetylation, methylation and so on of histones (proteins that the DNA are wound around). This can affect cell signalling and gene expression. For example, ROS can deplete SIRT1, which is a deacetylase that normally represses chronic inflammation, sensecence (cell aging) and apoptosis. When SIRT1 is depleted, it can no longer repress these processes, so cell aging, death and so forth become more prevalent.

Glycolysis and the Pentose Phosphate Pathway

Now we're getting into the nitty-gritty details! (At least it's pretty easy to see the relevance of this lecture though :P)

Describe the reactions of glycolysis and the mechanism of energy production in the cytosol.  

Glycolysis, as you should know, is a pathway in which glucose is broken down to form energy. The main end product of glycolysis is pyruvate, which has three different fates: in the presence of oxygen, it can be converted to acetyl-CoA and enter the citric acid cycle; in anaerobic conditions, it can form lactate; and in some organisms it can be broken down to ethanol (such as in the fermentation process in yeast).

Glycolysis has two major phases: the preparatory phase and the payoff phase. (Not sure if those are official names, but they're on the slides.) In the first phase, 6-carbon glucose is converted into two 3-carbon sugars called glyceraldehyde 3-phosphate. In the second phase, glyceraldehyde 3-phosphate is converted into pyruvate, generating ATP and NADH. It should be noted that glucose is not the only fuel that can enter this pathway: it's the main fuel, but other sugars can enter the pathway at different stages.

Phase 1: Preparatory Phase

The preparatory phase consists of five steps:

1. Glucose --> Glucose 6-phosphate. Requires ATP and the enzyme hexokinase.
2. Glucose 6-phosphate <--> Fructose 6-phosphate. Requires the enzyme phosphohexose isomerase.
3. Fructose 6-phosphate --> Fructose 1,6-bisphosphate. Requires ATP and the enzyme phosphofructokinase-1.
4. Fructose 1,6-bisphosphate <--> Glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Requires the enzyme aldolase.
5. Conversion of dihydroxyacetone phosphate into glyceraldehyde 3-phosphate (so you end up with 2 molecules of glyceraldehyde 3-phosphate for every molecule of glucose). Requires the enzyme triose phosphate isomerase.

Note that 2 molecules of ATP are required (steps 1 and 3). Don't worry- we'll more than make up for that later.

Phase 2: Payoff Phase 

The payoff phase also consists of five steps:

1. Glyceraldehyde 3-phosphate <--> 1,3-bisphosphoglycerate. Requires the enzyme glyceraldehyde 3-phosphate dehydrogenase. During this step, NAD⁺ is also reduced to NADH, with a little help from HPO₄^2- which supplies the hydrogen.
2. 1,3-bisphosphoglycerate <--> 3-phosphoglycerate. Requires the enzyme phosphoglycerate kinase. Produces ATP. (1 molecule of ATP is produced for each molecule of 1,3-bisphosphoglycerate, but since one molecule of glucose produces two molecules of 1,3-bisphosphoglycerate, you actually get 2 molecules of ATP for every 1 molecule of glucose.
3. 3-phosphoglycerate <--> 2-phosphoglycerate. Requires the enzyme phosphoglycerate mutase.
4. 2-phosphoglycerate <--> Phosphoenolpyruvate. Requires the enzyme enolase. Produces some water.
5. Phosphoenolpyruvate --> Pyruvate. Requires pyruvate kinase. Produces ATP (the ATP yield of this step is the same as the yield for step 2 of this pathway).

As you can see, this pathway has two ATP-producing steps (2 and 5). These steps combined produce 4 molecules of ATP for every molecule of glucose. As 2 molecules of ATP were consumed in the first half, this results in a net yield of 2 ATP molecules per molecule of glucose.

Explain the difference between reversible and irreversible reactions.

Reversible reactions are reversible while irreversible reactions are irreversible...? Also, the reversible reactions tend to have a small free energy change, whereas irreversible reactions have a much larger one (I think).

The three irreversible reactions in the glycolysis pathway are steps 1 and 3 of the first phase as well as the final step of the second phase.

Have an understanding of the purpose of the pentose phosphate pathway.

The pentose phosphate pathway produces pentose sugars, such as ribose 5-phosphate, that are required for the production of nucleotides (and, by extension, DNA and RNA). Along the way, NADPH is formed, which is required for biosynthesis of fatty acids and production of glutathione (GSH).

The first step of this pathway is catalysed by glucose-6-phosphate dehydrogenase (G6PDH). If this is deficient, the red blood cell membrane might be lost, leading to haemolysis and haemolytic anaemia.

Respiratory Reflexes

This lecture had a fair bit of new content. It's not as difficult conceptually as that last cardiovascular lecture, but it is still way too much for a Monday afternoon IMO :P (Okay, it wasn't that bad, but I feel like there were a few little bits and pieces that just slid past me.)

Describe the inputs to the central rhythm generator.

As mentioned in my previous post, respiratory rhythm arises largely from the medulla. The centres in the medulla involved in control of respiration can be influenced by a variety of factors, such as feedback from peripheral receptors, emotion and temperature. (Temperature doesn't really have a massive effect on ventilation in humans, but in some animals, such as dogs, it can cause panting.) Voluntary control of ventilation is separate to the rhythm control in the medulla.

List the three types of lung receptors

The three types of lung/lower airway receptors include slowly adapting receptors (SARs), rapidly adapting receptors (RARs) and C-fibres. I'll describe them in more detail soon.

Describe the Hering-Breuer reflex.

As mentioned here, the Hering-Breuer reflex prevents overinflation of the lungs. It does this by suppressing inhalation when the lungs are already inflated. The vagus nerve is vital to this reflex- if you cut it, the reflex disappears. The Hering-Breuer reflex is not particularly strong in conscious humans, but it is important in animals (and may also be important in anaesthetised humans).

Explain the role of SAR and their stimulation and effects.

SAR, or Slowly Adapting Receptors, help detect the volume of the lungs. They are activated when the lungs are stretched, and as they do not adapt to the stretch (or at least they adapt very slowly, hence their name), they keep firing while the lungs are inflated. These may contribute to the Hering-Breuer reflex, which I just described.

SARs are myelinated fibres which have a conduction velocity of 15-30m/s (which is pretty standard for myelinated fibres). As mentioned above, they are stimulated by stretch. They do not respond to deflation, unlike RARs as I'll discuss shortly. The effects of SAR activation include reduced tidal volume, shorter respiratory time and bronchodilation.

Describe the reflex effects of RAR and the stimuli that activate them

RAR, or Rapidly Adapting Receptors, help detect changes in volumes of the lungs. Located within or near the epithelium, they are activated when stretching occurs, but their response is rapidly "switched off." They respond in response to both inflation and deflation, and the frequency of their impulses depends on the rate of change of volume of the lung (which is also related to inspiratory flow rate).

RARs, like SARs, are myelinated fibres with a conduction velocity of 15-30m/s. As well as being stimulated by stretch, they are also stimulated by irritants such as acid, smoke and dust. They produce reflexes such as coughing, tachypnea (abnormally rapid breathing), hyperventilation and bronchoconstriction.

Describe the activation and reflexes produced by C-fibres.

C-fibres, unlike RARs and SARs, are unmyelinated and thus their conduction velocity is much slower (1m/s). They come in two flavours: bronchial and pulmonary. They are present in the airway epithelium, as well as in other places around the lung.

Stimulants of C-fibres include capsaicin (as I'll explain shortly), acid and/or hypertonic saline (for bronchial C-fibres) and oedema and/or large amounts of inflation (for pulmonary C-fibres). It should be noted, however, that they are generally not very responsive to inflation. Activation of C-fibres produces bronchoconstriction, bradycardia, and sometimes cough. Initially, C-fibre activation can produce apnoea, but later on hyperpnea can be produced instead. (See here if you don't remember what these terms mean.)

One thing that is kind of unique about C-fibres is that they contain both afferent and efferent fibres, allowing the signal to branch out more easily (I think... there were quite a few tidbits in this lecture that I didn't quite get). C-fibres also contain neurotransmitters, including peptide neurotransmitters such as tachykinins. These can cause vascular leak (contraction of endothelial cells, increasing the amount of space between them), mucous production and bronchoconstriction. (I think. As I said, there were quite a few bits in this lecture that slid over me. I blame the time in the afternoon.)

Recall the receptors activated by capsaicin.

C-fibres can be activated by capsaicin, the component of chilli that makes it hot. Capsaicin activates vallinoid receptors (VR1), which are TRP (transient receptor potential) channels. Activation of VR1s produces the sensation of heat. Over long periods of time, capsaicin can actually kill off C-fibres, making you more tolerant to hot foods.

Explain the detection of cough.

This was hardly covered in the lecture, but the summary slide says that RARs and maybe C-fibres can detect cough. Receptors in the upper airways might help as well.

Describe the effects and activation of upper airway cool receptors.

Receptors in our upper airways can respond to changes in temperature, such as what happens when we exhale air from outside. Stimulation of these receptors makes us feel like we are breathing, so receptor stimulation suppresses further ventilation. On the other hand, when these receptors are blocked, we can feel like we can't breathe even though our blood gas concentrations might be normal.

Aside from cool receptors, there are quite a few other receptors in the upper airway (nose and larynx). These can cause laryngospasm (closing off of the larynx). These receptors can respond to flow, temperature, pressure, upper airway muscle contraction, snoring and obstruction.

Describe the effects of menthol.

Menthol stimulates cool receptors, making it feel like you are getting more airflow than you actually are.

Explain the muscle proprioception reflexes including the spindle and tendon organ

Muscles have a couple of different proprioception reflexes. We didn't go into too much detail on them in the lecture though. Apparently this was covered to some extent in PHYL2002, which I didn't do, so...

Muscle spindles can measure muscle length, and sudden change in spindle length (as might happen when you tap someone on the knee) can cause a reflex contraction. The Golgi apparatus can also play a role in measuring force on the tendon. Such receptors are present in a lot of skeletal muscles, but the diaphragm has few of them. Hence, a lot of the proprioception reflexes involved in breathing actually come from the abdominal muscles and intercostal muscles.

Define dyspnea.

Dyspnea is the feeling that you can't breathe, even though blood gases might be normal. There are several different mechanisms that might trigger this, such as mucus covering the cool receptors (as happens during a cold).