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In order to cease neural transmission and reset the synaptic cleft, acetylcholinesterase (AChE) an enzyme
located in the synaptic cleft, destroys the ACh molecules, enabling the closing of the nicotinic receptor bond
cation channels, terminating the muscle response. Choline is transported into the axon terminal for
resynthesis of acetylcholine.
However there are circumstances where these steps do not always flow smoothly. One example of this is
Myasthenia Gravis, an autoimmune disease whereby the body produces antibodies that blocks these
Nicotinic Receptor Cation channels normally opened by the ACh. The result is that ACh has limited receptors,
and therefore limited success at stimulating the muscle. The overall result for the patient is extreme muscle
weakness and fatigue.
But the condition is not without treatment. One of the most common pharmaceutical treatments of
Myasthenia gravis is AChE Inhibitors ie. Neostigmine. By inhibiting the AChE in the synaptic cleft, it allows ACh
longer time to stimulate the few receptor channels that are available to it. This in turn allows for increased
muscle stimulation, closer to normal levels.
However AChE inhibitors are not without their side effect and can cause issues in the GIT like hypermotility.
This could lead to the need to take even further medication to counteract the side effects.
If the effects of the AChE inhibitor begin to lessen, or if the side effects begin to increase too much, then in
general the next option is plasmapheresis, whereby the antibodies causing the issue are extracted from the
blood completely. With reduced antibody levels, the symptoms of Myasthenia Gravis are often reduced,
however it can become a repetitive process.
Conclusion So as outlined, the neurotransmission across the neuromuscular junction is a well-choreographed mutli-step
process. However with conditions such as Myasthenia Gravis, there can be issues with the process, and while
symptomatic treatment is available, there is no cure yet.
Tell them what you’re going to tell them. Tell them. Tell them what you just told them. ~ Aristotle
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Tell them what you’re going to tell them. Tell them. Tell them what you just told them. ~ Aristotle
Aerobic
Reaction Path Intermediate ATP Produced
Glycolysis 2 ATP 2
2 NADH + H+ 6
Pyruvate -> Acetyl CoA 2 NADH + H+ 6
TCA Cycle 6 NADH + H+ 18
2 FADH2 4
2 ATP 2
Total 38
Anaerobic
ATP Produced
Glycolysis 2 ATP 2
2 NADH + H+ 6
Pyruvate -> Lactic Acid -6
2
Tell them what you’re going to tell them. Tell them. Tell them what you just told them. ~ Aristotle
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Tell them what you’re going to tell them. Tell them. Tell them what you just told them. ~ Aristotle
5. Discuss the critical role fluid balance plays in our bodies by considering the following headings:
a. Describe how body water is compartmentalized in the body
b. Describe the ionic composition of the body’s fluids
c. Explain what osmotic pressure means.
d. What determines the osmotic pressure of body fluids?
e. What unit is used to measure osmotic pressure?
f. Explain why changes in body fluid balance are so dangerous?
g. Detail what happens in the body as a result of dehydration of the body’s fluids.
Intro Approximately 60% of our body weight is fluid, and ensuring a balance of fluid in our bodies is critical and
over the next few minutes we are going see how our body regulated and balances the fluid levels.
Fluid constitutes 60% of our body weight and in newborn the percentage is even higher (75%). Therefore the
constancy of fluid composition is crucial for cell function. Over the next few minutes, we are going to see how
our body regulates and balances fluid levels.
Body Of the fluid, 2/3rd is intracellular, and 1/3rd is extracellular (predominantly in the form of interstitial fluid) with
just 20% of ECF as Plasma. Apart from water, these fluids consist mainly of electrolytes, which are almost
completely disassociated, and some negligible quantities of other biomolecules like amino acids and glucose.
In the ECF the electrolytes comprise of mainly sodium and chloride ions, while in the ICF the electrolytes are
comprised mainly of potassium and phosphate ions as well as proteins that are negatively charged. ECF
composition is critical for cell function, and is maintained by homeostasis, while ICF composition has
important influences on cellular reactions (bcs ionic strength has an important influence on cellular reaction)
and is maintained by mechanism within the cell itself.
Osmotic pressure of body fluids is a measure of the tendency for water to move into solution based on its
relative concentration of non –penetrating solutes and water. The higher the osmotic pressure of a solution,
the lower the water concentration and the higher the solute concentration of the solution. The electrolyte
concentrations in ECF and ICF play a large role in their osmotic pressures, in particular sodium and chloride
ions in (ECF) and potassium and phosphate ions in (ICF). The osmotic pressure of ECF and ICF is roughly equal,
resulting in no net movement of water between the two. Thus, ensuring that cell volume remains constant.
The osmotic pressure exerted by particles in a solution is determined by the number of the particles per unit
volume of fluid not by the mass of the particles and the unit used is osmole. Osmole refers to number of
osmotically active particles in a solution rather than molar concentration. 1 osmole (osm) is equal to 1 mole
(mol) of solute particles. However, the osmole is too large a unit to express osmotic activity of solutes in body
fluids, so milliosmole is used (mOsm). 1x10^-3
The exact osmolarity of body fluids is 283mOsm/L and control of free water balance is critical for regulating
body fluid osmolarity. Any changes to body fluid osmolarity can result in movement of water into or out of
the cells as water moves from a solution of low osmolarity to one of higher osmolarity until osmolarity in the
two solutions are equal. This can disrupt cellular function, and put additional strain on the body’s organs.
In cases of dehydration, water content of plasma and interstitial fluid (the entire ECF) decreases causing
increased concentration of ECF with a related increase in osmolarity of ECF. Water will then leave all cells by
osmosis through the cell membranes in order to increase osmolarity of ICF. This can cause disruption of
cellular function. Symptoms are mainly neurological as water loss from brain cells leads to shrinkage of cells.
Conclusion So we have seen how important it is to maintain the body fluid balance to avoid any problems that could
arise in the failure to do so, worst could be circulatory shock and death.
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Tell them what you’re going to tell them. Tell them. Tell them what you just told them. ~ Aristotle
DNA, Deoxyribose Nucleic Acid is a genetic material. Our genetic information is encoded by the sequence of
different nucleotide bases in DNA and is responsible for the development, operation and reproduction of all
living organisms. DNA synthesis occurs by the process of replication that happens most notably during the S
phase of cell cycle. But in order to produce functioning molecules for the body to function, DNA has to
undergo two more processes; transcription and translation.
Body Transcription is the process where Ribose Nucleic Acid, or RNA are synthesised from a DNA template and it
happens in 5’ to 3’ direction of mRNA (transcription occurs in 3’ to 5’ direction on DNA template –antisense
strand). Transcription occurs in 3 steps.
Steps of transcription:
The first step is initiation. An enzyme, RNA Polymerase, in closed complex form, binds to a promoter region
on the DNA which identifies the start of the DNA sequence to be transcribed. The RNA Polymerase then
changes to Open Complex form and in doing so unwinds a 17-18 base pairs segment of the DNA.
Next is elongation: RNA Polymerase moves along the “antisense” strand of the unwind DNA template
synthesizing mRNA until it reaches the terminator region. RNA Polymerase reads antisense strand of DNA in
3’ to 5’, making mRNA copy 5’ to 3’, matching the DNA bases with their RNA counterparts, similar to the
matching of base pairs in DNA Replication, but with the notable difference that DNA’s thymine is replaced by
uracil in RNA.
Lastly is termination: When the RNA Polymerase reaches the Terminator region of the DNA strand, it causes
the RNA Polymerase to stop, disassociate from the DNA and release the mRNA. Forces in the DNA cause it to
wind itself back together again, returning it to its original form.
The mRNA however is not the end product; it will then undergo translation. Translation is the synthesis of
proteins directed by a mRNA template in a ribosome with the help of tRNA. The Ribosome itself is made up of
Ribosomal RNA and a variety of proteins, and is split into 2 units, the small unit and the large unit.
Translation also occurs in 3 steps;
Initiation: Amino acids are matched to the mRNA through in sets of 3 nucleobases known as codons. The
small and large ribosomal units assemble around the mRNA. Charged initiator tRNA that is tRNAMet enters
the P site and binds to the start codon AUG which code for methionine on the large subunit. AUG is the
codon for amino acid Methionine or the start codon. The variable portion of the protein starts after that. The
protein chain begins.
Elongation occurs by the binding of the next aminoacyl-tRNA to the large unit of ribosome in line with each
next codon in turn. In this way ribosome is repeatedly moving in steps of 3 nucleobases at a time along the
mRNA. Peptidyltransferase reaction takes place, forming bond between the previous amino acid & incoming
amino acid and the peptide chain beings to grow. As each amino acid joins to the chain the tRNA linked to
the previous amino acid detaches and uncharged tRNA exits the ribosome through E site.
Termination: The peptide chain growth continues until the ribosome reaches a “Stop Codon” (UAA, UAG,
UGA). The tRNA linked to the stop codon contains no amino acid, and therefore when the penultimate tRNA
detaches from its associated amino acid, the peptide chain is released from the P site of ribosome and the
ribosome dissembles from the mRNA.
As each codon is made up of 3 nucleobases, and there are 4 different RNA nucleobases, this allows for 64
different codons (4x4x4). However, there are only 20 standard amino acids, meaning that some amino acids
link to more than 1 Codon. But if you were to take a section of mRNA that codes for 10 codons, the first being
AUG/Methionine and the last being the Stop codon, despite its small size, it can still code for in excess of 25
billion different amino acid combinations.
Conclusion Therefore, while there are several intricate steps to be taken to convert a DNA sequence into a protein, the
end results and possible combinations are vast. However the number and intricacies of the steps required
also allow for several sites for mutations to occur and this may cause deadly effects.
Tell them what you’re going to tell them. Tell them. Tell them what you just told them. ~ Aristotle
Translation- Elongation
Transcription
Images to Promoter Transcription start site Ploy A termination
Transcription start site Stop codon
Draw 3’ 5’
5’ 3’ 5’ 3’ mRNA
Transcription factors bind A U G U U UG G AG U G … U G A
TF A A A C C U
3’ 5’
5’ 3’
RNA polymerase
Transcription elongation
3’ 5’
5’ 3’
RNA polymerase
Met Phe Gly
3’ 5’
DNA
5’ 3’
5’ 3’ mRNA Translocation
Ribosome moves along 3 bases and mRNA
specifies next amino acid (aa). tRNA
RNA sequence is complementary to template strand
Tell them what you’re going to tell them. Tell them. Tell them what you just told them. ~ Aristotle
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Tell them what you’re going to tell them. Tell them. Tell them what you just told them. ~ Aristotle
8. Receptor signalling and ligand-receptor interactions. Using tamoxifen as an example, discuss receptor signalling and
inhibition. Tamoxifen is a partial agonist on the oestrogen receptor and is used in the treatment of breast cancer.
a. What are an agonist and an antagonist?
b. Describe the structure of the oestrogen receptor?
c. Describe the events that follow when oestrogen binds to its receptor?
d. What is a partial agonist and what is the consequence of using a partial agonist such as tamoxifen?
e. Is there an option of using a pure antagonist?
Intro As the name implies, receptors are protein molecules that receive chemical signals from outside a cell.
Receptor binding triggers intracellular signalling cascades with protein –protein interactions and enzymatic
reactions. These cascades regulate metabolic enzymes, membrane transporters, ion channels and genes. We
will now be looking at a specific case of this, in the oestrogen receptor, which is one of the receptors targeted
in the treatment of breast cancer. Without treatment, the receptor, on binding with oestrogen, encourages
breast cancer cells to multiple.
Body First, we will look at the stimulation of these receptors. Hormones or other extracellular signalling molecule
that binds to receptors are said to be either agonists or antagonists. In their simplest form agonist stimulate
the receptors, causing biological response while antagonists inhibit the stimulation of receptors. Agonists
acting as accelerators, antagonists acting as brakes. They can work together acting on different receptors or
in competition for the same receptors.
Oestrogen is a type of lipophilic hormone, it uses intracellular gene –specific transcription factors. The
intracellular receptors for this hormone is structurally similar and are referred to as the steroid hormones
superfamily of receptors and are primarily localised to the nucleus thus the oestrogen receptor is called a
nuclear receptor, which comes in 2 forms, alpha and beta. Both forms contain the same 5 sections along its
length as follows:
- The N Terminal domain, including Activation Function 1
- The DNA Binding Domain (DBD)
- The Hinge domain
- The Ligand Binding Domain, including Activation Function 2
- And the C Terminal Domain
After the oestrogen binds to its receptor, the ligand binding domain changes its shape and displaces the heat-
shock protein (chaperon protein) complex that had been inhibiting its action. With the protein complex
displaced it allows for the binding of cofactors (both co-activators and co-repressors) to the receptor, which
help to promote its interaction with DNA target genes, making use of both Activation Function 1 and 2 (AF1
and AF2). Oestrogen binds to the receptor like a lock and key after it has passively diffused into the cell
forming a hormone receptor complex then moves into the cell nucleus through nuclear pores.
Partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the
receptor relative to a full agonist. They may also be considered to display both agonistic and antagonistic
effects - when both a full agonist and partial agonist are present, the partial agonist actually acts as a
competitive antagonist, competing with the full agonist for receptor occupancy and producing a net decrease
in the receptor activation observed with the full agonist alone. In the case of Tamoxifen, the natural
oestrogen in estradiol when bound the oestrogen receptor promotes a fully activated transcription, both AF1
and AF2, whereas Tamoxifen only promotes a partially activated transcription (via AF1). Meaning that there is
still some DNA transcription taking place in the breast cells thus it can be useful to treat early and advanced
oestrogen recptor- positive (ER+) breast cancer because breast cancer cells require oestrogen to grow.
As an alternative, Fulvestrant is a pure antagonist used in treatment of advanced breast cancer in
postmenopausal women. It blocks dimerization and nuclear localisation of the oestrogen receptor, reduces
cellular levels of oestrogen receptor and blocks gene transcription completely (neither AF1 nor AF2)
-have similar structure to oestrogen, can interact with immunoassays fro blood estradiol concentrations and
show falsely elevated results thus can improperly lead to discontinuing the treatment.
Conclusion While Tamoxifen goes some way to inhibiting the action of Oestrogen at the Oestrogen Receptors in breast
cancer cells, it is not without its issues, firstly that it is only a partial agonist, leads room for further issues, but
in addition to that, it also has been found to have differing effect on different tissue types, where in the
Endometrium it has been found to actually increase the risk of uterine cancer.
While Fulvestrant improves on some of these issues, it has other issues itself, one primary example being the
Tell them what you’re going to tell them. Tell them. Tell them what you just told them. ~ Aristotle
cost, which can be several hundred times greater than alternative solutions. These elements would have to
be considered when taking into accounts a patient ability to fund their treatment.
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9. Compare and contrast Ipratropium and Salbutamol in the treatment of patients with bronchoconstriction.
a. Use your knowledge of agonists and antagonists to explain how these drugs serve to alter sympathetic tone
in the lungs.
Intro Bronchoconstriction is found to occur in conjunction with several medical conditions, one of the more
common and widely known conditions being asthma. In bronchoconstriction, the lung airways constrict due
to the tightening of surrounding smooth muscle. Loads of factors could cause the tightening of the muscles
but inhibiting the muscle tightening is one of the primary treatments in reversing bronchoconstriction. We
will now look at two of the pharmaceutical treatments used in inhibiting or reversing bronchoconstriction,
Salbutamol and Ipratropium.
Body Salbutamol is referred to as a beta 2 agonist. To start off, we need to look at the different types of receptors
in the body. The two main categories are Nicotinic Receptors and Muscarinic Receptors, both are adrenergic
receptors. (adrenoreceptors are G-protein coupled receptors) The Nicotinic receptors are further subdivided
into Alpha and Beta-receptors, and both of these, as well as Muscarinic receptors, and further subdivided to
5 different types. These receptors are found in varying levels through the body, and are used in the control of
varying different bodily functions. Salbutamol has a specific focus on the Beta 2 receptors as its target.
Next, we will look at the stimulation of these receptors. Chemicals and molecules that has effects on these
receptors are said to be either agonists or antagonists. In their simplest form Agonist stimulate the receptors,
acting as accelerators and antagonists inhibit the stimulation of receptors, acting as brakes. They can work
together or in competition for the same receptors, or together acting on different receptors. Salbutamol, as
mentioned, is a Beta-2 Agonist, meaning that it acts to stimulate the Beta 2 receptors. Stimulation of these
receptors causes the muscles in the airway to relax and dilate, causing bronchodilation which is the opposite
of bronchoconstriction
The second pharmaceutical treatment we will look at is Ipratropium, which is referred to as a muscarinic
antagonist. As outlined earlier, Muscarinic receptors is one of the main groupings of receptors, which is
subdivided into M1 to M5. However, unlike Salbutamol, which specifically targets Beta 2 receptor,
Ipratropium targets the entire Muscarinic range, and has been found to do so equally from M1 to M5.
As mentioned Salbutamol acts in a stimulatory capacity as an agonist, whereas Ipratropium acts as an
antagonist, meaning that Ipratropium blocks the stimulation of the muscarinic receptors from naturally
occurring stimulations. The stimulation of the muscarinic receptors in the lungs causes constriction of the
smooth muscles, and as such inhibiting this stimulation will lessen the constriction of the muscles, and the
overall bronchoconstriction.
Conclusion So although Salbutamol, a Beta-2 agonist, and Ipratropium, a muscarinic antagonist target different receptors
in the lungs, and act on the receptors in different ways, they are both used in the inhibition or reversal of
bronchoconstriction. A benefit of their differing modes of action is that they can both be administered
without impeding on the action of the other. It is for this reason that they are at times administered together
in order to increase the chances of reversing the bronchoconstriction.
A drawback is that they also have some similar side effects, including headaches and dry mouth, so a
combined treatment with both, is increasing the likelihood of these side effects. However the benefits, both
of individual treatment, and combined treatment are generally seen to outweigh the drawbacks. So much so
that both medications are included in the World Health Organisation list of Essential Medicines
Images to N/A – Potentially a table just outlining targets or each, and mode of action
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Tell them what you’re going to tell them. Tell them. Tell them what you just told them. ~ Aristotle