SUMMARY DECK Flashcards
1
Q
- Briefly outline the difference between genetics and genomics
A
genomics is the study of genomes and their evolution, and genetics is the study of heritability such as how a trait get passed onto offspring
2
Q
- Describe the relationship between the genetic code and protein structure
A
the genetic code determines the amino acids that are translated from the DNA, and these amino acids create proteins. Therefore, the protein’s structure is directly influenced by the amino acids involved and therefore also the genetic sequence.
3
Q
- Describe the way in which genes are encoded using the three-letter codon
A
genetic strands are translated 3 nucleotides at a time, which creates an amino acid. + there are stop and start codons, which determine how many amino acids are involved in a gene.
4
Q
- Briefly outline the structure of DNA and list the bases, pyrimidines, and purines, that interact as base pairs.
A
DNA is held in a double helix made of sugary molecules. This double helix is bound together by complementary base pairs of nucleotides. For example, the purine nucleotide A binds with the pyrmidine nucleotide T. G also pairs with C respectively. + This is all within the chromatin of the nucleus of a cell, and it forms the code that is used to make proteins.
5
Q
- Define the terms gene and pseudogene.
A
a gene is a single unit of heredity. A psudogene is a partly or completely non-functional gene due to a genetic mutation. + Pseudogenes aren’t able to produce a protein, and this could be because thei lack a start codon or have a premature stop codon.
6
Q
- Describe the structure of the human genome including details of the currently accepted number of genes, regulatory RNAs and pseudogenes.
A
there are 20 amino acids that are used to make proteins in the body. There are 80,000 to 400,000 proteins in the body. There are 21,306 protein coding genes. 21,000 genes.
7
Q
- Describe the difference between the technical meanings of the words ‘mutant’ and ‘variant’.
A
A mutation is a single change in the DNA strand, and this might not cause the resulting protein from a gene to change its functioning in any way. A variant is where one or more mutation in a strand causes the resulting functioning of that gene to change However, the term variant is more commonly used when interacting with patients because mutant has negative connotations.
8
Q
- Briefly outline the main categories of genetic variant.
A
benign, pathologic, loss of function, gain of function. Benign is one that has not yet been linked with a condition or disease, however it is possible to be in the future due to further genetic research. Pathologic is where the change in the genetic sequence causes a change in the resulting amino acid and protein that has been linked to having a mechanism that causes or worsens a disease or contition. Loss of function is where the resulting protein of a gene is completely or partially non functional. Gain of function of where the resulting protein from a gene strand gains a new function, or already existing functions are enhanced.
9
Q
- Outline the major mechanisms observed in the generations of genetic variants (mutants) including sense and non-sense single nucleotide variants (polymorphisms), frame-shift variants, indels, structural variants and copy number variants.
A
– single nucleotide varients are where a single nucleotide in a sequence is changed and replaced. There are 2 types: missense are where the nucleotide is replaced with a different nucleotide, and nonsense is where the nucleotide is replaced with a stop codon. This can cause the translation of a gene to be prematurely stopped, so is a frame-shift variant- deletions can also result in these type of varient. Indels are where there is an insertion or deletion of a nucleotide in a gene strand. Structural variants include: large deletions (where more than one nucleotide is deleted from a genetic strand), inversions (where a nucleotide is taken out of a genetic strand and put back in backwards), translocations (where more than one nucleotide are removed from a strand and replaced), and copy variants (where a nucleotide is put into a genetic strand too many times). Repeat number variants are where too much of a protein is made from a gene, which can block neurons and causes reductions in motor control.
10
Q
- Define the terms meiosis and mitosis.
A
meiosis is cell division of sex cells, into 4. mitosis is cell division making 2 identical daughter cells.
11
Q
- Briefly describe the major causes of gene mutation.
A
sexual reproduction, random events, mutations
Variation caused by sexual reproduction is heritable, and is caused by genetic recombination events. Random genetic variation is not heritable as it happens during normal cell division or during the life of a cell, and it is usually inappropriate DNA repair mechanisms following any damage. Mutagens are things that cause mistakes in genetic coding. They can be pollutants / environmental triggers, viral insertions (viruses insert their own dna into our cells) or even radiation
12
Q
- Describe how epigenetics can affect the expression of coding genes within the genome
A
this is the study of how gene activity can be controlled without changing the DNA sequence itself- when a person has certain lifestyle choices and behaviour such as smoking and exercise, specific genes can become METHYLATION. This is where chemical tags are added to C nucleotides on the DNA to alter the activity of the gene. When enough C-nucleotides on a genetic strand are METHYLATED, the gene will be switched off and it will no longer be able to exert its affect and create its amino acid and protein. Epigenetic factors can also bind to histones, which alters the extend to which DNA can wrap around it. This means the gene woont be transcribed as well.
13
Q
- Briefly outline how a blood test for a monogenetic disorder is set-up using PCR.
A
a monogenetic disorder is one caused by a single gene mutation. To test if someone has a variant in the specific gene involved, a sample of blood is taken, and the gene involved is compared next to the ‘normal’ gene. If there is variation to the gene in the patient’s sample, the gene will be a different length to the ‘normal’. This is because, for example, a deletion would cause the gene to be smaller as it lacks a nucleotide.
14
Q
- Describe the term ‘genome bioinformatics.
A
this is the storage and analysis of genomic data on a computer. It is big data as it includes data from a large amount of people, and it helps to analyse differences in people’s genomes.
15
Q
- Outline some of the main goals of healthcare genomics.
A
it helps inform the best therapeutic decisions, identify people at risk of certain diseases, helps create prevention services, helps create treatment strategies, provides more accurate diagnosis
16
Q
- Understand be able to define key terms, parenchyma, hypoxia, hyopxaemia, hypercapnia, acidosis, alkalosis
A
parenchyma (lung tissue),
hypoxia (lack of oxygen in tissue),
hypoxaemia (lack of oxygen in tissue)
hypercapnia (too much co2 in blood),
acidosis (where the blood becomes acidic due to more co2 or H+ ect. pH lower than 7.35)
and alkalosis (where blood becomes alkaline, the pH is more than 7.45)
17
Q
- Define the difference between restrictive and obstructive lung disorders
A
restrictive is where it is harder for the patient to breathe in, usually because the lungs have less space to expand, so they don’t reach vital capacity- eg interstitial lung disease. Obstructive is where it is easy for the patient to breathe in but hard for them to breathe out. This happens when something inside the lungs stops the air from leaving, so it gets trapped and causes hyperinflation of the lungs- eg COPD.
18
Q
- Describe the pathology associated with chronic obstructive pulmonary disease (COPD), including the details of emphysema and chronic bronchitis.
A
COPD is an obstructive lung disorder where there is a loss of radial traction due to damaged parenchyma and an increase of mucus production. Emphysema causes the destruction and enlargement of alveoli airspaces. This is because neutrophils and macrophages phagocytose smoke when it enters the alveoli of the lungs. This causes the cells to change their behaviour to become more defensive, so they release serine elastase. This breaks down the elastin in the tissue, but this happens uncontrollably as a product of the engulfed smoke is reactive oxygen species, which along with the smoke itself, inhibits the action of alpha1-antitripsin. This means than excessive amounts of serine elastase is released, damaging and enlarging the alveoli. Chronic bronchitis is the inflammation of the bronchi. Smoke particles cause goblet cell hyperplasia, so they release excessive mucus, however this cannot be cleared from the bronchi as smoke damages the cilia on the epithelium. This means that the mucocilliary escalator is not fully functioning, and means that the patient needs to cough to clear the mucus. Inflammation happens because the mucus is likely to become infected, and the inflammatory response causes general edema and causes fibroblasts to lay down fibres that restrict the elasticity of the bronchi. There is also disorganised growth of stem cells, so squamous cells are produced instead of colomner cells so theres a lack of cilli in this way.
19
Q
- Describe the role of Alpha-1 antitrypsin and Alpha-1 antitrypsin deficiency in the development of COPD
A
– alpha1-antitripsin controls the release of serine elastase, which breaks down the elastin in tissue. A deficiency in alpha1-antitripsin means the production is no longer regulated, so mass destruction of elastin in tissues can occur. Reactive oxygen species and smoke can cause this, and there could be a genetic linkage.
20
Q
- Describe how the Reid index is calculated and it’s relevance to tracking the pathophysiology of chorionic bronchitis
A
the reid index measures the depth of a mucus gland compared to the thickness of the submucosa. So, it can track the severity of chronic bronchitis, however it is usually done post mortem.
21
Q
- List key examples of obstructive lung disorders
A
- e.g. COPD, bronchiectasis and asthma
22
Q
- List key examples of restrictive lung disorders
A
e.g. diffuse pulmonary fibrosis, pneumothorax, scoliosis
23
Q
- Define the difference between intrinsic and extrinsic restrictive pulmonary disorders and list key examples
A
intrinsic restrictive pulmonary disorders are ones where the cause of the restriction to the extend the lungs can inflate is due to changes from within, for example fibrosis of lung tissue. Extrinsic restrictive pulmonary disorders is where the lung is unable to inflate due to there being a lack of space around the lungs to do so, for example interstitial lung disease and scoliosis.
24
Q
- Describe the pathophysiology of diffuse pulmonary fibrosis
A
this is where fibroblasts lay down fibres in the interstitial space around the lungs, as well as collagen fibres being deposited. This limits the extent the lugs can inflate due to a lack of elasticity. If this becomes chronic, fibroblasts can invade the alveoli and, which can section off areas and cause a collapse.
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12. Briefly outline the role of the lungs in helping maintain acid-base balance within the body
the lungs aid the pH within the body to remain at 7.4. this is because they maintain a balance of oxygen and carbon dioxide in the tissue and blood. However, if there is too much carbon dioxide in the blood, bicarbonate cannot alone maintain homeostatic control, so more H+ ions are recruited to transport the CO2 out of the body. Hydrogen causes the blood pH to decrease as it is acidic.
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13. Briefly describe the key difference between respiratory acidosis and alkalosis.
respiratory acidosis is where there is increased carbon dioxide in the blood. Respiratory alkalosis is where there is decreased carbon dioxide in the blood.
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14. Briefly describe how the respiratory system can compensate for a state of acidosis
hyperventilation is an attempt to increase oxygen levels, and force carbon dioxide out of the blood
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15. Outline the key effects of ageing within the respiratory system
decreased SA for gas exchange to occur, decreased lung compliance, decreased lung elasticity, increased alveoli size, stiffening chest wall, mitochondrial dysfunction
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1. Define the term ‘congenital heart condition’
developmental heart defects that occur as a foetus is growing. Severe defects can be fatal, but not severe ones may not be detected until after birth, or even years in the future.
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3. Be aware of the general categories of congenital heart defects outlined in this presentation
congenital atrial defects, congenital ventricular defects, congenital valve stenosis, patient ductus arteriosus. Small defects are hydrodynamically irrelevant as there is high resistance against it. However large defects can cause volume overload and reverse the flow of blood.
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5. Describe the features of arial septal defects, VENTRICULAR SEPTAL DEFECTS, CONGENITAL VALVE STENOSIS, PATENT DUCTUS ARTERIOSUS
arial septal defects (L to R shunt causes blood to recirculate the pulmonary circulatory system, so doesn’t pose issues with oxygenation),
ventricular septal defects (same as before but the hole is between the wall of the 2 ventricles- interventricular septum- rather than the atrium),
congenital valve stenosis (where the valves are narrower than ‘normal’. This can cause a lack of blood flow in the systemic circulatory system, and even leaky valves. If this is serious, a valve replacement surgery is needed) and
paten ductus arteriosus (this is where the ductus arteriosus doesn’t close before birth, and can cause pulmonary hypotension and volume overload in the pulmonary circulation system.
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6. Describe a range of acquired heart conditions in childhood as outlined in this presentation
DILATED CARDIOMYOPATHY is where the heart stretches and becomes enlarged. When the ventricles stretch it reduces their ability to pump blood around the body effectively. Myocarditis is the inflammation of the myocardium, this is usually due to an infection, and it restricts the hearts ability to pump blood effectively, and can affect heart rhythem. Pericarditis is the inflammation of the pericardium, this restricts the amount of space available around the heart to allow it to pump due to increased fluid around it, and it usually due to a viral infection. Endocarditis is the inflammation of the valves of the heart, and is usually due to bacteria in the blood stream. This can reduce the amount of blood available to be pumped around the body and can cause leaky valves.
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7. Describe the pathophysiological features and complications of atherosclerosis in adults.
atherosclerosis is the formation of plaques in damaged blood vessels, which reduces the space blood has to flow. When a blood vessel is damaged from foreign particles such as smoke, inflammation occurs. low density lipoproteins carry cholesterol to the area as they are small enough to pass through the membrane into the circulatory system, and there the lipids oxidise. This damages surrounding tissue so macrophages use LDLs to turn itself into foam cells, and these drop their lipid content at the site. Collagen fibres are also dropped at the site as well as immune cells. smooth muscle cells replicate and cover this content, forming the fibre cap. The plaque can grow due to blood vessels invading the area and bleeding into it- this can cause the plaque to rupture. Blood clots can also form because the plaque creates a turbulent flow, and these can blood flow to areas of the body. This can cause major complications if it happens in one of the main blood vessels surrounding the heart as necrosis could occur.
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8. Briefly describe the pathophysiological features of early atherosclerosis in childhood.
arterial fatty streaks where LDLs invade the area. Immune cells also have symptomatic changes.
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9. Describe a range of aetiologies and risk factors for atherosclerosis.
it is mainly associated with adult behaviours such as diabetes, obesity, smoking, living in a polluted area. But, high childhood BMI and cholesterol can also be risk factors.
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10. Describe the pathological features of angina pectoris.
this is where blood supply to the heart is limited due to a narrowing in the blood vessels. This can be due to the growth and rupture of an atherosclerotic plaque.
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11. Outline the difference between low-density lipoprotein (LDL) and high-density lipoprotein (HDL) and which of these constitutes a major risk factor for the development of atherosclerosis.
A low density lipoprotein carries cholesterol to a site of damage in a blood vessel. This is because it is small enough to pass through the membrane into the circulatory system, so it is a major risk factor for the development of atherosclerosis. However, high density lipoproteins are too large to pass through the membrane, so they carry cholesterol to the liver instead to be processed.
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12. Define and explain the term coronary arterial stenosis.
this is where there is narrowing to the coronary artery. This causes a reduction in the amount of blood that is carried to the heart.
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13. Briefly outline the main consequences of myocardial ischemia. –
this means that the myocardium does not receive enough oxygen and nutrients. Waste products will not be able to be removed which can create a toxic environment. Also, the lack of nutrients means there will be mitochondrial dysfunction as they will not be able to provide enough energy to the heart, so it can cause problems with impulse formation and conduction.
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14. Describe the key pathological features of myocardial infarction (MI) and explain a range of complications following MI
myocardial infraction is commonly known as a heart attack. It is where there is a sudden drop in the amount of blood the heart receives. This causes pain in the chest because it causes inflammatory mediators to be released and nociceptors are activated. If the person is left without their heart beating for too long, the brain wont get enough oxygen and it can cause neurological problems.
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15. Explain what is meant by S -T segment elevation in the context of coronary artery blockage
tissues in that area areent able to repolarise or depolarise properly.
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16. Define and explain the term ‘cardiac arrhythmia’.
this is where there is irregularity to the beating of the heart. This can be caused by problems with impulse formation or conduction, or both – so there are abnormalities in the electrical system in the heart
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17. Define the terms ‘tachycardia’ and ‘bradycardia’
tachycardia is abnormally fast breathing heart, and the other is abnormally slow.
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1. Describe the terms ‘pain, nociception and pain perception’.
pain is the body’s warning system to actual or potential danger, and it changes our behaviour to avoid it- it is an unpleasant sensory and emotional experience. Nociception is the encoding of noxious stimuli- it is the neuronal connections to the brain in response to the activation of a free nerve ending. Pain perception is the brain’s response to nociceptive signals, and it tells us how severe the damage is. This can vary depending on things like priorities, psychological state, and past experiences.
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2. Explain the difference between nociception and pain perception.
nociception is the chemical signals that are sent to the brain once free nerve endings are activated, and pain perception interprets these signals to tell us how bad the damage is. Our brain generates the pain experience, making it subjective.
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3. Explain the difference between the direct and indirect spinothalamic tract.
the direct spinothalamic tract sends nociceptive signals to the somatosensory system via the thalamus, however the indirect spinothalamic tract diverts signals from the thalamus to the limbic system and the brainstem. This limbic system creates an emotional response to the signals, and the brainstem adjusts cardiac output and sweating in response to the signals.
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4. Describe the International Association for The Study of Pain (IASP) definitions of pain e.g.,
how pain can be highly subjective because the encoding of pain relies heavily on the brain’s interpretation of the damage according to past experiences and psychological state. So, the same pain stimuli can create different pain responses in different people.
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5. Explain the neuromatrix theory of pain.
many areas of the brain get involved in creating a response to nociceptive signals, which means that many aspects can affect how badly we feel pain. For example, fears, attitucdes, psychological status.
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6. Explain the concept of pain as a multifactorial phenomenon
e.g., how several factors are involved in the perception of pain such as distractions, mood, ect
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7. Describe the course and the nature of the information transmitted by Aδ and C fibres from the periphery to the cortex
delta fibres transmit nociceptive signals faster than c-fibres because they are myelinated, which means they are insulated to improve how fast electrical signals can pass through- c-fibres aren’t myelinated. A-delta fibres also have a larger axonal diameter than c-fibres.
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8. Explain why pain is always a personal, subjective experience.
due to the multifactorial things and neuromatrix things
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9. Define the terms allodynia and hyperalgesia.
hyperalgesia is increased sensitivity to a noxious stimuli, and often occurs when there is continuous damage to the tissue. Primary hyperalgesia is where this sensitivity is only at the side of damage, and secondary hyperalgesia is where sensitivity expands to the area surrounding the damaged tissue that isn’t damaged itself. Allodynia is where a person feels pain, and nociceptive signals are coming from an area where no damage has occurred. This occurs because glial cells can switch inhibitory input to excitory output, so they can trigger a nociceptive situation
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10. Briefly outline the different types of pain
visceral, deep somatic, superficial somatic.
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11. Describe the difference between chronic and acute pain states.
Acute pain lasts less than 3 months, and goes away when the damage to the tissue is repaired. Chronic pain is pain lasting longer than 3 months, and remains even after the damage to the tissue has been repaired. This means that it can cause lifestyle changes to accomodate
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12. Briefly describe/discuss the pain gate theory
this is the theory that rubbing an area that is painful reduces the pain experience. This is because we have a-beta fibres on the skin that sense touch, and when these are activated they cause ENKEPHALINS to be released at the spine. This IS A INHIBITORY TRANSMITTER THAT blocks nociceptive signals reaching the brain, and so reduces the pain experience.
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13. Briefly describe the spinothalamic tract, that it contains three neurons, where these neurons have their cell bodies, where they synapse and what kind of information this tract carries.
the spinothalamic tract carries nociceptive signals to the brain. There are 3 neurons involved. The first has its cell body in the dorsal horn, the second in the spine, and the third in the thalamus. They carry nociceptive information
the direct spinothalamic tract carries info on temp, pain, and crude touch. When a nerve ending is activated, the first order neuron is the first nerve cell to pick up this pain. The action potential is passed across a synapse to the second order neuron, which has its cell body in the spine. This second order neuron passes the mid line of the body and sends its axon up the spinal cord to the thalamus. The thalamus acts as an info depot, and the second order neuron sends the info across the synapse to the third order neuron. This then carries action potential to the somatosensory neuron.
However, there is also an indirect spinothalamic tract. Pain info is carried through the thalamus, but instead of going to the somatosensory cortex, it is diverted to other parts of the brain such as the brain stem and limbic system. Pain info is also carried to the imigdella, which helps us understand the significance of a pain – emotionally and in relation to a previous experience of pain in that area.
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14. Describe descending modulatory pain pathways and outline how they function.
The descending modulatory pathways in the pain system can control the levels of nociception and therefore how badly we feel pain. Neurons in the brain stem send efferent fibres down the spine, which release serotonin and norepinephrine in the spine. This triggers endorphins to be released and reduce the amount of nociceptive signals that can travel up the spinothalamic tract, so reduce the central perception of pain. This reduces the pain experience.
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15. Describe how free nerve endings are activated:
how they act as nociceptors when they are activated by inflammatory mediators. – when a tissue is damaged, the free nerve endings are activated by the degradation of mast cells into serotonin for example.
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16. Describe the phenomenon of peripheral sensitisation.
How is substance P release triggered and how it can set up a positive feedback loop leading to sensitisation. – when a tissue is constantly damaged, FREE NERVE ENDINGS trigger the release of substance P. this causes an increased amount of inflammatory mediators to be released AS MAST CELLS DEGRANULATE AND RELEASES HISTAMINE. So, this increases the activation of free nerve endings, but it also causes a positive feedback loop. This is because with increased activation, more substance P will be released, and this leads to increased activation.
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17. Outline the phenomenon of neuropathic pain, including central and peripheral damage to the nervous system and how this can lead to the perception of pain. Describe neuropathic pain using the example of a herniated disk
neuropathic pain is pain due to damage to the somatosensory system. This can be caused by a herniated disk as it can put pressure on the spinal cord, and so prevenet how well the somatosensory system functions.
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18. List four key psychological factors that can affect pain perception including
- perceived threat, attention, expectation, and experience.
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19. Explain why humans need the ability to perceive pain.
so that we can avoid pervieved or actual danger. This is a survival adaptation
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20. Explain the concept of referred pain.
pain felt in an area of the body other than the source of the nociceptive signals. This happens because the neuronal network is set at the embryo developmental stage. In this stage, areas of the body are much closer together than when a person is fully developed as an adult. These neuronal connections remain when a person is an adult, so can mean that 2 first order neurons with different origins can connect to the same second order neurons in the spine. In this way, pain can be perceived to be in a different place than its actual origin.
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21. Explain the difference between Aδ, Aβ and C fibres.
. A-delta and C fibres are free nerve endings that respond to noxious stimuli, however a-delta ones carry nociceptive information faster because they are myelinated and have a larger diameter axon. A-beta fibres are free nerve endings on the skin that respond to a touching sensation, and this can reduce the perceived pain in an area because it stimulated endorphins and serotonin to block nociceptive signals in the spine.
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1. Describe the gross and ultrastructural features of Alzheimer's disease pathology
there is a loss of brain tissue, which causes larger gaps between folds of brain tissue LEADING TO COGNITIVE IMPAIRMENTS. On a cellular level, there are neurofibrillary tangles and amyloid plaques, which lead to this loss of brain tissue. Due to a genetic mutation in the APP gene, THE AMYLOID PRECURSER PROTEIN IS ENCODED FOR, AND ENZYMES CAN SEPARATE BETA AMYLOID FROM THIS. This causes beta amyloid to be secreted out of the cell, and it folds into fibrils in the intracellular space- creating amyloid plaques. However, due to a genetic mutation in the MAPT gene, tau protein in the cytoplasm of cells becomes phosphoralised and therefore insoluble. This causes the microtubule network to be unable to regulate the distribution of neurotransmitter across the cell, and is how neurofibrillary tangles form. THIS CAUSES NEURODEGENERATION, AND IT CAN BE SPREAD ACROSS NEURONS AS FILAMENT FRAGMENTS CAN TRAVEL ACROSS A SYNAPSE AND SEED INTO THE CONNECTING NEURON.
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2. Outline the amyloid cascade hypothesis of Alzheimer’s disease
AMYLOID PLAQUES ARE THE PRIMARY CAUSE. this is the hypothesis that the development of amyloid plaques is the cause of alzheimer’s disease. This is because the precurser protein is encoded by a gene mutation. Also, the production of plaques can trigger tau protein to be phosphoralised. However, other studies have shown that there is no correlation between the amount of amyloid plaques and severity of the symptoms of alzheimers- it is merely present in the disease.
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3. Outline the Tau hypothesis of Alzheimer’s disease
SAYS THAT TAU PHOSPHOROLATION IS THE PRIMARY CAUSE. the amount of neurofibrillary tangles is positively correlated with the severity of symptoms of alzheimers. This means that it has a stronger linkage to the disease than amyloid plaques.
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4. List and briefly describe key issues associated with ageing of the brain
hippocampus generates new cells more slowly than old ones die, this leads to a loss of brain tissue and memory impairments (CONNECTION BETWEEN CELLS WEAKEN). The autoimmune system is more slow at responding to internal changes in the body DUE TO BRAIN STEM SLOWING PROCESSING DOWN. The blood brain barrier is less effective, so an older person is less able to defend against pathogens damaging the brain
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5. Outline the main aetiological and pathological features of bacterial meningitis
this is the inflammation of the meninges. Bacteria can cross the blood brain barrier through defects (eg parahippal cortex) or perforations, and enters the cerebral spinal fluid between the pia mater and arachnoid mater. It then releases toxins that kill NEURONS, which triggers an inflammatory response. This creates pressure on the brain, which is reinforced by the accumulation of dead immune cells that together are pus. This pressure cannot be counterbalanced by the drainage of cerebral spinal fluid because the pus blocks this from happening. so, inflammation causes high amounts of pressure on the brain and if this gets too high then a herniation can occur.
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6. Explain the difference between primary and secondary brain injury –
primary brain injury is the initial insult where the tissue of the brain is displaced. Secondary is the brain’s response to this. For example, the inflammatory response
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7. Outline key examples of primary and secondary brain injuries.
primary is a haemorrage, secondary is a herniation due to higpressure.
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8. Outline the Monro-Kellie Doctrine
this is the relationship between the volume of the contents of the cranium and pressure within the cranium. The ‘normal’ volume of the cranium is 1700ml- volume of brain tissue, blood, and cerebral spinal fluid need to equate to this. If one of these factors has a rise in volume, the others need to decrease theirs to compensate for this. For example, a rise in tissue volume due to a brain tumour needs to be compensated for by venous of cerebral spinal fluid drainage.
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9. List the three signs of Cushing's triad
crushings triad is the 3 symptoms that are indicators that a patient has too high intracranial pressure. Rising BP – when the hypothalamus has LACK OF NUTRIENTS AND OXYGEN, THE sympathetic NS causes PERIPHERAL vasoconstriction. To PARASYMPATHETICALLY compensate for this, the heart creates a slowing pulse. Slowed respiration also happens because high pressure on the brain stem causes changes in respiration.
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10. Describe two key mechanisms of intracranial pressure compensation
venous drainage and cerebral spinal fluid drainage
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1. Describe the concepts of drug/ligand binding and binding affinity
binding affinity is how well a ligand binds to a receptor to activate a response. Full agonists activate the complete response from the receptor, while partial agonists only activate a partial response. To bind well, a steric interaction needs to occur, which means that the shape of the binding reigons of both the ligand an receptor need to be physically compatible. The ligand and receptor also need to have opposite electrostatic charges to be attracted to each other. Finally, the ligand needs to be lipophilic if they are trying to bind to a receptor inside a cell membrane, as membranes are hydrophobic so they cannot be hydrophilic.
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2. Briefly outline how genetic variability can affect ligand binding and what impact this can have on personalised healthcare –
genetic variation can cause differences in the binding site of the receptor, so a drug might have a reduced effect. This means that it might not work well enough to produce a therapeutic response in the body.
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3. Describe why the molecular structure of a drug, its molecular target and the characteristics of the target tissue are important in determining the action of the drug in the body
To bind well, a steric interaction needs to occur, which means that the shape of the binding reigons of both the ligand an receptor need to be physically compatible. The ligand and receptor also need to have opposite electrostatic charges to be attracted to each other. Finally, the ligand needs to be lipophilic if they are trying to bind to a receptor inside a cell membrane, as membranes are hydrophobic so they cannot be hydrophilic.
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4. Describe the four common classes of protein targets for drugs
enzymes (prodrugs bind to become activated, false substrates bind to create a product that itsnt fully functional, and enzyme inhibitors bind to stop the enzyme from activating other substances. DRUGS BIND TO ENZYMES TO STOP CHEMICAL PROCESSES FROM WORKING PROPERLY IN THE BODY) , carrier molecules (drugs bind to them to stop them from being able to carry other molecules across a cell membrane), ion channels (drugs can either block these, or bind to receptors on them to control the transfer of nutrients) and receptors (drugs can bind to these to activate them SO THAT THEY CHANGE THE WAY THE CELL FUNCTIONS)
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5. Describe what is meant by the term drug-specificity and how it links to non-specific drug effects
drug specifity is how well a drug can bind to a single receptor. Most drugs bind to several receptors in the body, and this becomes increasingly likely with higher doses. This is why a drug can have many non-specific effects.
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6. Explain the processes of absorption, distribution, metabolism and elimination.
absorption- the process by which the drug reaches the systemic circulation. It is affected by the route of administration and permeation (the ways the drug molecules can permeate tissues) drugs most be soluble and in a solution to be absorbed into the systemic circulation. Distribution – there are 3 factors affecting distribution: protein binding, blood flow to the tissues, and membrane permeation. In terms of protein binding, an ingested drug can bind to plasma proteins in the plasma water, but only the unbound fraction of the drug can cross membranes or bind to receptors. Drugs are only bioavailable if they are unbound, because these are the molecules that are small enough to diffuse through capillary walls and so produce a pharmacological effect. We need to be aware that a drug might have more of a profound effect in a patient who is malnourished because more of the drug will be unbound and therefore bioavailable. The rate at which a drug gets to a blood rich area of the body is much faster than in an area with less blood supplying it. According to Fick’s law, the higher the surface area of a membrane, the faster the exchange of a substance. Also, uncharged ions diffuse more efficiently than charged ions, so non-ionised drugs will have better access to membrane bound compartments. Finally, a drug needs to be lipophilic because the area inside the membrane is hydrophobic, so a hydrophilic drug wont be able to pass through. Metabolism - usually involves converting drugs into an inactive form in the liver. However, pro-drugs are actually activated by metabolism, such as codeine into morphine. There are 2 phases, which do not occur in any set order, and some drugs only need to go through one of the phases to be ready for excretion. Excretion - most drugs are excreted by the kidneys in the renal system. Only unbound drugs can be processed via glomerular filtration as anything bound to a protein will remain in the blood. Biliary excretion is the main route.
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7. Describe phase one and phase two metabolism
phase one metabolism is where the drug is chemically transformed to deactivate it so that it no longer can have a pharmacological effect, make it water soluble, and polarise (charge) it. Phase 2 metabolism is where toxins are covalently bonded to other substances, and they are made water soluble. Not every drug goes through both phases, and the phases don’t happen in any set order.
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8. Explain why first-pass-metabolism is an important consideration for understanding the effect of drugs in the body
first pass metabolism is where a proportion of drugs administered via an enteral route will never be absorbed, so will never have an effect on the body. This is because it is eliminated straight away. THIS IS THE PROBLEM WITH ENTERAL ADMINISTRATION ROUTES, SO THE DOSE NEEDS TO BE ALTERED TO TAKE THIS INTO CONSIDERATION
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9. Outline the different routes for drug administration
enteral is routes that will be absorbed vis the gastrointestinal tract eg oral and rectal. These undergo first pass metabolism, but they are easy to administer and there is low risk for infection as the GI tract already has barriers to infection. THEY NEED A WAXY/POLYMER COASTING SO IT DOESN’T GET DAMAGED BY THE HARSH CONTENTS OF THE STOMACH. Parental routes is where is isn’t absorbed via the GI tract eg injections. These avoid first pass metabolism, but there is a high risk of infection as the skin is being broken. TOPICAL CREAMS ARE ALSO AN EXAMPLE- THEY CAN BE USED FOR LONG TERM DOSES AND HAVE LOW RISK FOR INFECTION, BUT THEY CAN CAUSE SKIN IRRITATION.
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10. Explain the terms protein binding, bioavailibility, billiary excretion, half life
protein binding (some of a drug administered will bind to plasma proteins, however only the unbound proportion of the drug will be bioavailable and ready to exert an effect),
bioavailability (the proportion of an unbound drug in the blood after administration. Injections have a high bioavailability straight after administration, however tablets don’t as they have to be absorbed),
biliary excretion (where a drug is excreted by the body via the biliary system in the kidney. Only the unbound proportion of the drug can be excreted this route. Drug metabolites are put into the bile in the duodenum and excreted in the foeses)
and half-life (the time it takes for the drug to reduce to 50% bioavailability in the blood. Most drugs take 5 half lives to be almost or completely excreted).
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1. Describe the general mechanism of action, range of administration routes and possible side effect of corticosteroids –
corticosteroids are anti-inflammatory drugs, but they can also reduce pain and increase function and motility. They do this by binding to receptors in the cytoplasm of cells, and then migrating to the nucleus so that it can control the translation of the DNA held inside. This therefore controls what proteins are produced. In this way, corticosteroids ensure arachidonic acid is not produce from the fatty acids released in damaged tissue. This prevents the arachidonic acid cascade from occurring earlier than NSAIDs, so it reduces peripheral sensitisation and reduced the pain experience. Without arachidonic acid, inflammatory mediators are not released, so this is how corticosteroids reduce inflammation. These can be administered through topical patches and creams, as well as injections and tablets. However, corticosteroids can disrupt the hypothalamic-pituitary-adrenal axis. This can cause issue with the adrenal system, weight LOSS, and psychological issues such as euphoria and depression.
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2. Describe the mechanism of action for local anaesthetics such as
local anaesthetics work by diffusing into axon cell membranes and blocking the v-gated sodium channels from within. This prevents the axon from creating action potential, so no nociceptive signals are send to the CNS. In this way, they provide a loss of pain and sensation in the specific area it is administered to. One issue is that around 50% of the drug is charged outside the cell, so it cannot diffuse across the cell membrane. Only uncharged drug can pass the membrane, and it becomes charged once inside as a response to a change in pH, and becomes trapped in the cell.
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3. Describe how drug partitioning is a key process in the activity of local anaesthetics such as lidocaine
The partition coefficient is the measure of the lipophilicity of a drug and an indication of its ability to cross the cell membrane. , a drug needs to be lipophilic because the area inside the membrane is hydrophobic, so a hydrophilic drug wont be able to pass through.
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4. Outline the mechanism of action for common antibiotics such as the penicillin-like drugs and erythromycin.
penicillin like antibiotics are a group called beta lactam antibiotics. They work by blocking the action of an enzyme that builds the cell wall in gram positive bacteria. This damages them as they rely on their cell wall for cell integrity, and without it the cell will fall apart and die. However, erythromycin targets gram negative bacteria as it doesn’t have a cell wall as its outermost layer, its cell wall is between 2 membranes. This works by blocking an essential binding pore as well as the function of bacterial ribosomes. Without bacterial ribosomes working properly, the bacteria will not be able to translate its bacterial RNA properly, so the cell dies.
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5. Describe some of the key mechanisms by which antibiotic resistance can occur or spread
acquisition of new genes, natural selection, random mutations. Acquisition of new genes is where bacteria can spread their resistance genes by making physical connection to another bacteria strain or species using an f-pili, and pass across their plasmid. VIRUSES PREY ON BACTERIA AND INSERT THEIR GENETIC CODE IN THE, WHILE THEY DO THIS THEY CAN PICK UP A BACTERIUM’S RESISTANCE GENE AND SPREAD IT ACROOS MORE CELLS. Natural selection describes how antibiotics kill less resistant bacteria faster, which gives more resistant bacteria the perfect environment to grow if the full course isn’t taken. Random mutations refers to any insertions, deletions, or copy variants that can occur in bacterial DNA. This can cause: differences to the binding site on bacteria, so antibiotics cant interact with it anymore; antibiotic-inhibiting enzymes to be released by the bacterium, and changes to membrane permeability so the antibiotic gets pumped out or isn’t allowed in to the bacterial cell.
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6. Define the term ‘pharmacogenomics’
the study of how variations in the human genome can change how a patient can react to drugs. For example, mutations can cause differences in a receptor’s active site, and also cause changes to the absorption, metabolism, and excretion processes.
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7. Describe one example of how genetic mutation can lead to differences in drug response within a population -
CYP2D6 gene variant – 15% of the population have variants of this gene, which is responsible for the metabolis processing of many drugs. The variant can lead to higher or lower than expected bioavailability of the unbound drug in the bloodstream. You can identify people with variants using microarray technology, which identifies variants of interest, and is a fairly rapid test as a treatment tool.
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1. Explore the different terms used to describe a patient’s engagement with their rehabilitation or medical treatment –
COMPLIANCE IS THE EXTENT TO WHICH A PERSONS BEHAVIOUR MATCHES WITH MEDICAL/HEALTH ADVICE- THE HEALTH PROFESSIONAL MAKES DECISIONS AND THE PATIENT IS EXPECTED TO FOLLOW. ADHERENCE IS WHERE PATIENTS ARE A BIT INVOLVED IN THE DECISION MAKING PROCESS ABOUT THEIR HEALTH. CONCORDANCE IS WHERE THERE IS TOTAL PARTNERSHIP AND AGREEMENT BETWEEN HEALTH PROFESSIONAL AND PATIENT.
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2. Explore the impact and consequences of not engaging with rehabilitation or a medical treatment –
– WASTE OF MEDICAL RESOURCES, REPEATED DOCTOR VISITS, MORE COMPLICATIONS/SIDE EFFECTS, MORE OCCURANCE OF PREVENTABLE DISEASES.
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3. Start to explore the possible reasons why patients may not engage in their rehabilitation or medical treatment –
– POOR SOCIAL SUPPORT, DEPRESSION, ANXIETY, GREATER PERCIEVED BARRIERS, UNEMPLOYMENT, LACK OF EDUCATION, DENIAL, INTERRUPTION TO DAILY ROUTINES, SIDE-EFFECTS, LITTLE OBVIOUS BENEFIT.
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4. Identify ways to encourage engagement amongst patients
– COMMUNICATION, EDUCATION, SHARE RESOURCES, PROVIDE EASY ACCESS ASSISTANCE, ADDRESS BARRIERS, WORK IN PARTNERSHIP, RECOGNISE ALL PATIENTS ARE INDIVIDUALS.
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1. Re-cap pain theory and understand peripheral and central processes
PERIPHERAL SENSITISATION : Continued damage to the tissue causes peripheral sensitisation, which is a positive feedback loop that acts as a vicious cycle. Persistent activation of free nerve endings causes them to release substance P, which is a powerful vasodilator that triggers neurogenic inflammation. It also activates mast cells, which degranulates and releases histamine. This increases the activation of free nerve endings, so causes the cycle to complete as more substance P is released, and this all happens again. This increases the pain experience.
CENTRAL SENSITISATION : Continuous damage to the tissue also causes central sensitisation, which can increase the intensity of the pain experience due to NMDA receptors. In the spine, the first order neuron releases glutamate as its main neurotransmitter across the synapse. It activates cell surface receptors on the second order neuron called AMPA receptors. This lets positive ions into the cell, which triggers the second order neuron to send action potential to the thalamus. However, with continuous damage to the tissue, an increasing amount of glutamate is released and a second set of cell surface receptors on the second order neuron are activated. These are called NMDA receptors, and trigger the second order neuron to be more responsive, so making it more sensitive. This increases the pain experience.
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3. Describe all three levels of the WHO pain ladder, explaining it’s relevance to pain management
WE START WITH THE LESS EFFECTIVE ANALGESICS AND MOVE UP TO THE MOST EFFECTIVE WHEN IT COMES TO CHRONIC PAIN. BUT WE WORK THE OTHER WAY ROUND WHEN IT COMES TO SEVERE ACUTE PAIN. BASICALLY WE USE THE LOWEST EFFICACY DRUG TO REDUCE THE PAIN. FOR MILD PAIN, NON-OPIOIDS ARE USED. FOR MODERATE PAIN, WEAK OPIOIDS ARE USED. FOR SEVERE PAIN, STRONG OPIOIDS ARE USED. WE TEND NOT TO USE THIS LADDER ANYMORE COZ IT PUT PEOPLE ON DANGEROUSLY HIGH LEVELS OF OPIOIDS.
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4. Describe the mechanism of action of NSAIDs and paracetamol
NSAID drugs such as Ibuprofen and Aspirin block cyclooxygenase (COX) enzymes in the human body. There are thought to be three types of cyclooxygenase enzyme in humans, COX-1, COX-2, and COX-3- but the existence of COX-3 has only been showed in animal studies. COX enzymes play a key role in the arachidonic acid cascade. When tissue is damaged enzymes (phospholipase A2) convert fatty acids into arachidonic acid. COX enzymes can bind to arachidonic acid and convert it to a series of intermediary molecules. The range of intermediaries produced depends on the specific cells and tissues involved. However, eventually these intermediaries are converted into a group of chemicals called prostanoids which include prostaglandins and thromboxanes. Prostaglandins are key inflammatory mediators that can activate and sensitise free nerve endings and trigger the key signs of inflammation. Thromboxanes are involved in regulation of haemostasis (blood clotting). In general, the main mechanism of action of NSADs is to block COX enzymes. By blocking production of prostaglandins NSAIDs can reduce their availability to activate free nerve endings and thus act as analgesics and anti-inflammatories. By blocking production of thromboxanes they can act to reduce haemostasis. Prostaglandin production in the brain is also involved in the development of fever, so blocking prostaglandin production there can result in the antipyretic effect of many NSAID drugs.
Its key to note that aspirin irreversibly binds to COX enzyme with a covalent bond. So, to overcome the effects of aspirin new COX enzymes will need to be produced. Other NSAIDs reversibly bind to a COX enzyme as they hop on and off the COX.
PARACETAMOL : It provides relief from pain and fever. It doesn’t effectively inhibit COX enzymes in peripheral enzymes, so it is not an anti-inflammatory- which is why it is not technically an NSAID. However, it does target COX-2 enzymes in the CNS, and there is some evidence that it increases the activity of descending modulary pathways. Paracetamol breaks down in 2 phases. The product of the first phase is very toxic, so the second phase needs to happen fast before it can damage the liver. However, the metabolite in the second phase is available with a limited daily supply, so an overdose of paracetamol will occur if a person ingests too much compared to the amount of the second metabolite available.
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Describe the mechanism of action of mild and strong opioids
An opioid is a compound that has similar physiological effects to opium, this means that is downregulates the excitability of nociceptive pathways. For a drug to be an opioid it has to bind to specific opioid receptors and mimic the action of the neurotransmitters involved. For example, endorphins and enkephalins. Mild opioids are less efficient at activating receptors, whereas strong opioids activate the receptors well. Strong opioids tend to have a higher potency, binding more strongly or interacting with higher efficacy. They activate the receptors more strongly. There are a range of receptors that opioids can bind to, including Mu and delta receptors on free nerve endings, and kappa receptors in the spine. When one of these receptors are activated, it triggers a cascade in which nerve cell excitability is reduced, so their ability to send nociceptive signals is reduced. This caused analgesia (pain relief). When this happens at the receptors of free nerve endings in peripheral reigons, it reduces the likelihood of peripheral sensitisation and inflammation.
Opiate receptors are found on the first order neuron in the spine, and when activated reduce the release of the neurotransmitter glutamate across the synapse. This reduces the sensitivity of the first order neuron. The opioid drug also binds to opiate receptors on the second order neuron, which also reduced its sensitivity. Therefore, the reduction of sensitivity causes a reduction in the nociceptive signals sent to the brain, and so reduces the feeling of pain.
Opiate drugs can also act in the brain. One key area is that they can act to increase the activation of descending pain modulatory pathways. This would lead to a reduction in nociceptive signalling to the brain and a possible reduction the intensity of the pain experience. Also, opioids can reduce the perception of pain by stimulating reward pathways in the brain.
Side effects: Euphoria (dysphoria in some people), physical dependence, constipation, vomiting and nausea, depression of cough reflex, respiratory depression, tolerance effects. Longer term issues include immune suppression, decreased sex hormone production, opiate induced hyperalgesia.
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cystic fibrosis
It is an obstructive disorder- meaning that patients who have this find it easy to inflate lungs but difficult to expel, so the lungs tend to hyper inflate. It is caused by a mutation of the CFTP gene on chromosome 7, where delta F508 amino acid is deleted in the genetic sequence.
CFTR is a chloride ion transporter, so variants in this can cause defects in the whole transportation process: an epithelial cell pumps out a chloride ion into its surface using ATP, but this cannot happen when there is a CFTR variant. The cellular defects caused by variants include defects in protein production and processing, as well as defects in the function and regulation of the pump.
Airway obstruction is a key issue in cystic fibrosis, as well as defects in antimicrobial defences. There is reduces chloride secretion, which causes increased sodium reabsorption into epithelial cells, and water also follows the sodium. Mucus in the lung becomes more sticky and dehydrated, so it sticks to the surface of the lungs. This causes a change in the pH of the bronchial epithelia- creating a defect in antimicrobial defences.
In the respiratory system, mucus can plug bronchioles, which can then cause the alveoli to collapse- this seriously affects ventilation perfusion coupling and gas transfer. This can then cause a lung abscess if there are large areas of the lung that have collapsed. Cystic fibrosis can also cause bronchiectasis, which is a widening of the airway due to mucus restricting the amount of air that can pass. The mucus can cause bacterial infection, leading to inflammation and airway destruction, creating scarring of the airway wall- which thickens it.
Aside from the lungs, cystic fibrosis affects multiple other systems. It can cause abnormal sweat production, chronic inflammation of the pancreas, and autoimmune damage to the biliary system in the liver due to blockage. It can also obstruct the vas deferens in men, which leads to sterility.
Cystic fibrosis can cause pathological complications in the lung, such as chronic airway infection, pulmonary fibrosis, and chronic respiratory failure. It can also cause cysts that rupture, creating widespread tissue destruction.
