What are the 4 components of the CNS?
1. The vertebrate nervous systems functions to detect, relay, integrate and respond appropriately to conditions in the outside world. 2. It is composed in the main of glia and neurones, of which glia are the more numerous 3. Glia play a wide variety of roles: structural support and shock absorption 4. Neurones are electrically excitable cells able to convey, integrate and respond to stimuli by changing the resting membrane potential.
What is the generalised structure of nerve cells? Explain the roles of their different functional regions.
Information arrives at the cell body of a neurone via dendrites where it is assimilated and processed. - Dendrites receive information from axons of other cells and convey it towards the cell body. - Processed information is then digitised and transmitted along the axon. At the end of the axon the information is passed to the target (muscle or neurone) via boutons (swellings at the end of the axonal process that make contact with other neurone cells or muscle.) There is a large variation in neuronal phenotype: multipolar (most abundant in CNS), bipolar & pseudounipolar neurons exist
The speed at which the nerve impulse travels along the axon depends what two main factors? Describe how these factors affect the speed.
1. The DIAMETER of the axon 2. Whether the axon is MYELINATED or not The larger the diameter of the axon, the lower the resistance is. - Passive movement of charge along the axon is easier with less resistance, therefore larger axons have faster passive charge movement. The more surface area there is on an axon, the higher its capacity to store charge across its membrane. - Capacitance is the amount of charge accumulated the membrane, the ability to maintain a steady state charge across the membrane. - The higher the capacitance the harder it is for charge to cross over the membrane, i.e. to overcome the repellant force of charge accumulated there. - The characteristics of an UNMYELINATED axon are a compromise between these two factors.
Define (i) action potential threshold (ii) absolute refractory period (iii) relative refractory period.
(i) The point at which a depolarising stimulus must reach for an action potential to be generated. (ii) The cell cannot be stimulated to its threshold potential, all Na+ channels closed (inactivation gate). (iii) A stronger stimulus than normal could induce an action potential, some Na+ ready but more K+ channels are open than usual, cell is still hyperpolarised.
What is the role of supporting cells (Schwann cells and oligodendrocytes) in speeding impulse conduction velocity through saltatory conduction?
SCHWANN CELLS - Form the myelin sheath around peripheral axons (PNS). A single Schwann cell forms the myelin around an axon for a single internode of one neurone. OLIGODENDROCYTES - Form the myelin in the CNS (white matter). These cell types have different embryological origins and so produce myelin which has differences in chemical composition. Multiple Sclerosis attacks oligodendrocyte myelin and so the CNS is differentially affected.
What does the voltage dependent Na channel help to do?
Set the refractory period of the action potential
How does an action potential move along an axon?
It’s a combination of passive diffusion currents along the axon and active currents through ion channels
What are the holes in the axons? Why are they there?
The holes are ion channels which are always open. These are essential to set the resting membrane potential of the cell
Define the terms (i) local circuits and (ii) saltatory conduction applied to nerve axons.
(i) LOCAL CIRCUITS (currents) - Voltage gated Na channels open and allow positive Na ions into the axoplasm. These ions set up a more positive potential which, when great enough, causes the next Na channel to open. - As the current leaks across the membrane, the magnitude of the depolarisation is degraded. Larger diameter axons with fewer channels transmit faster than narrow axons or ones with more channels – leaky undersea cable. (ii) SALTATORY (jumping) CONDUCTION - In this situation, the local currents can extend further as the normal leakage is curtailed by the myelin sheath. In this way the conduction of the nerve impulse flows rapidly through the inside of the axon to the node, where it slows and ionic depolarisation (action potential) takes place. Note only a few ions are needed to do this so there is an energy saving. And then the fast conduction along the inside of the axon resumes afresh.
What is the relationship between the sodium pump and action potentials?
The sodium pump is not involved in the action potential itself. - it fine tunes the resting membrane potential, and makes the final potential about 3mV more depolarised than diffusion alone would
In myelinated fibres, where are action potentials produced?
node of Ranvier
What is the code that is used in the CNS?
The action potential frequency
What are the 5 components of illness representation (illness beliefs)? Describe/Explain them.
1. IDENTITY = Symptoms experienced by the person as well as person’s label for the disease (pts/drs own diagnosis/label) I have a cold (‘the diagnosis’ = ABSTRACT), with a runny nose and cough (‘the symptoms’ = PERCEPTUAL) 2. CONSEQUENCES = Pts perceptions of the possible effects of the illness on their life. E.g. physical, emotional, financial, social ...“My cold will prevent me from going to the pub on Friday night, which will prevent me from seeing my friends” 3. TIMELINE = Pts beliefs about how long illness will last, whether it’s acute, chronic, or cyclical “My cold will be over in a couple of days” 4. CAUSE = Perceived cause of illness, e.g. biological (virus etc), or psychosocial (stress or some health behaviour such as smoking) “My cold was caused by a virus” OR “I got a cold because I was very stressed and run down” 5. CURE/CONTROLLABILITY = Pts beliefs about whether illness can be cured and the extent to which the outcome of their illness is controllable (by themselves or by powerful others) “If I rest and drink lots of fluids, my cold will go away” OR “If I go get medicine from my doctor, my cold will go away”
What are the 3 steps involved in the concept of self-regulation?
1. Identification of the goal: e.g. getting to school in time for class in the morning. 2. Selecting a strategy to achieve that goal and implementing: e.g. drive 3. Decide whether the implemented strategies achieved the goal or not . If not, try another strategy. E.g. take the bus
What is health promotion?
The process of enabling people to increase control over, and improve, their health.
What are the 3 major health challenges?
Smoking Obesity Alcohol
What are downstream and upstream influences on health? Explain them both.
DOWNSTREAM INFLUENCES are individual-level determinants or immediate causes such as: - Exposures (e.g. hazardous neighbourhood settings, infectious agents, adverse life events, etc.) - Behaviours (e.g. smoking, diet, exercise, etc.) - Personal strengths or vulnerabilities (e.g. coping styles, resilience, etc.) UPSTREAM INFLUENCES are social determinants or the “causes of the causes” such as: - Population-wide influences (e.g. education, taxation, labour and housing markets, crime and policing) - Most fundamental causes are international political and economic forces, and the forms of social stratification in a given society.
Explain top-down and bottom-up approaches to health promotion.
TOP-DOWN = Priorities set by health promoters who have the power and resources to make decisions and impose ideas of what should be done. BOTTOM-UP = Priorities set by people themselves identifying issues that they perceive as relevant
Describe the 5-tier public health impact pyramid.
On the health impact pyramid as there is an increasing population impact (top to bottom) this is looking upstream. Conversely looking at the bottom to top (increasing individual effort needed) this is looking downstream
What are the 5 approaches to health promotion? Describe them.
1. MEDICAL APPROACH: Aim - Free from smoking-related disorders (e.g. lung disease, heart disease, etc.) Activity: Primary prevention - Prevent onset of illness (e.g. encouraging non-smoking) Secondary prevention - Prevent progression of illness (e.g. smoking cessation) Tertiary prevention - Prevent further disability and suffering in those already ill (e.g. patient education, etc.) 2. BEHAVIOUR CHANGE: Aim - Change from smoking to not smoking Activity - Persuasive education - Prevent non-smokers from starting - Persuade smoker to stop 3. EDUCATIONAL APPROACH: Aim - Promote understanding of the effects of smoking on health to inform decision whether to smoke or not (and act on that decision) Activity - Provide information about effects of smoking - Help explore values and attitudes and come to a decision - Help learn how to stop smoking (if they want to) 4. EMPOWERMENT APPROACH: Aim - Smoking only considered if identified as a concern by the "community" Activity - Identify what (if anything) can be done about smoking (cessation or initiation prevention) 5. SOCIETAL CHANGE APPROACH: Aim - Make smoking socially unacceptable or make the healthy option (not smoking) the easy option Activity: Healthy public policy = Smoke-free policy = Increase age of smoking = Increase tax on tobacco products = Limit tobacco advertising and sponsorship
Define the following basic epidemiological terms (i) mortality rate (ii) incidence (iii) prevalence (iv) patterns of outcome occurrence (v) outcomes (vi) exposures.
(i) The no. of deaths in a given area/period, or from a particular cause. Meaningful statistics need: 1. A denominator pop (health board, city, hospital, recruited to a study) 2. Time-frame (person-time, n-year follow up) WITHOUT these death rates are meaningless (ii) Number of new cases in a specific time period. Rate = no.new ppl w.outcome over time period / total no.ppl in group at risk * 100,000 (iii)The proportion of a population found to have a condition. Point = at a specified time. Period = over a specified time period (iv) Sporadic= occasional cases occurring irregularly Endemic= persistent background level of occurrence (low to moderate level) Epidemic = occurrence in excess of the expected level for a given time period Pandemic = epidemic occurring in or spreading over more than one continent. (v) Death, Hospitalisation, First diagnosis with a disease, Recurrence (e.g. cancer), Quality of Life, Surrogates (e.g. blood pressure, lung function etc.) (vi) Non Modifiable = Age, sex, genotype. Modifiable = smoking, weight, diet, alcohol consumption. Interventions = a special kind of exposure. E.g. drug therapy, surgery, lifestyle advice.
How do you calculate and interpret appropriate effect estimates?
Risk = (No. outcomes in group / No. people in a group) x 100 Relative Risk (RR, Risk Ratio) = Risk in exposed / Risk in unexposed Relative Risk Reduction (RRR) = (1-RR) x 100 Absolute Risk Reduction (ARR, Risk Difference) = Risk in unexposed - Risk in exposed. Number needed to treat (NNT) = 1 / Absolute Risk Reduction
Describe and interpret confidence intervals.
Thought of “as a range of possible values” Presented for any statistic/effect measure Values near limits less plausible than those in middle Wider the interval, greater the uncertainty Useful in appraising published research
What is meant by confounding and bias?
CONFOUNDING: True relationship “confused” by a third factor. BIAS: Systematic error = What data are collected, How data are collected, How data are analysed, How data are interpreted, How data are reported Bias leads to wrong conclusions concerning: Effectiveness and Causality
Describe the hierarchy of evidence, and differentiate the various epidemiological study designs (HINT: there's 4.)
1. CROSS SECTIONAL STUDY: Sample a population Estimate the population: Different exposures Different signs/symptoms Different outcomes Use data: To descirbe prevalence/burden To explore associations 2. CASE-CONTROL STUDY: Select cases with an outcome Select controls with the outcome Explore EXPOSURES in cases and controls Identify association 3. COHORT STUDY Select people without an outcome Classify according to an exposure Follow up: Prospective Retrospective Compare RISK of disease in exposed and unexposed. 4. RANDOMISED CONTROLLED TRIAL (RCT) Random allocation: Intervention Control/comparator Compare RISK of outcome in intervention and control groups.
What are the 9 criteria for inferring causality? Describe them.
1. STRENGTH (effect size) - A causal link is more likely with strong associations 2. CONSISTENCY (reproducibility) - A causal link is more likely if the association is observed in different studies and different sub-groups 3. SPECIFICITY - A causal link is more likely when a disease is associated with one specific factor 4. TEMPORALITY - A causal link is more likely if exposure to the putative cause has been shown to precede the outcome 5. BIOLOGICAL GRADIENT- A causal link is more likely if different levels of exposure to the putative factor lead to different risk of acquiring the outcome 6. PLAUSIBILITY - A causal link is more likely if a biologically plausible mechanism is likely or demonstrated 7. COHERENCE - A causal link is more likely if the observed association conforms with current knowledge 8. EXPERIMENT - A causal link is very likely if removal or prevention of the putative factor leads to a reduced or non-existent risk of acquiring the outcome 9. ANALOGY - A causal link is more likely if an analogy exists with other diseases, species or settings
What factors affect utilisation of health services? (HINT: there's 6 factors)
physical, physiological, social, environmental - differences in symptom perception - influence of prior experience, lay referral - individual health beliefs and ideas held (HBM) - cost-benefit evaluation of seeking medical attention - social and emotional factors - quality of relationship with doctor
What 4 factors affect an individuals symptom perception?
1. strength of underlying physical sensation 2. tendency to pay attention to internal states 3. degree to which external stimuli competes for attention 4. variety of cognitive, social, emotional processes
What are the various types of health service user? Describe them.
1. AGE: infants and young children, elderly 2. GENDER: woman vs men > pregnancy and childbirth > focus on physical state 3. CHRONIC REGULAR USER: diabetes, asthma etc 4. ACUTE REGULAR USER: broken arm etc
Define treatment delay. What are the 3 stages that typically occur in treatment delay? Describe them.
TREATMENT DELAY= time that elapses between 1st perception of symptom and when person enters medical care. 1. APPRAISAL DELAY = time a person takes to interpret a symptom as an indication of illness (delay: sensory experience of symptom) 2. ILLNESS DELAY = the time between recognising one is ill & deciding to seek medical attention (delay: thoughts about symptom, new?) 3. UTILISATION DELAY = time after deciding to seek medical care until actually going in to use that health service (delay: benefits and barriers.)
What is the structure used when taking a pts history?
Presenting complain (PC) History presenting complaint (HPC) Past medical history (PMH) Drugs/allergies Family history (FH) Social history (SH) Systemic Enquiry
What is the ICE model used when taking a patients history?
Ideas, Concerns, Expectations “Do you have any thoughts yourself as to what may be the problem?” “Is there anything you are particularly worried that it might be?” “What are you hoping that I am going to be able to do for you today?”
What are the names of the 5 regions of the vertebral column? Mention how many vertebrae make up each region
Cervical 7 Thoracic 12 Sacral 5 (fused to 1) Coccygeal 3/4 (fused to one or two)
What forms the secondary curvatures of the spine?
What movement is greatest/most prominent in the (i) cervical (ii) thoracic (iii) lumbar regions?
(i) Flexion is the greatest movement, with some lateral flexion (ii) Rotation (iii) Extension is greatest m’ment, then flexion and some lateral flexion, but no rotation
Describe the atypical vertebrae; (i) atlas (ii) axis.
(i) Anterior (short) and Posterior (long) Arches, between two lateral masses, but no body Superior Articular Facets – concave oval to reciprocate with the occipital condyles Flexion and Extension of the head at the atlanto-occipital joint (ii) Body, with Odontoid Process or Dens, for articulation with the anterior arch of the atlas Vertebral Foramen large, triangular Superior Articular Facets – flat and circular to reciprocate with the inferior facets of the atlas Bifid spine and transverse process', with foramen Rotation of the head and neck at the atlanto-axial joint
What is the structure of zygapophyseal facet and intervertebral joints?
FACET: synovial with fibrous capsule and supportive ligaments INTERVERTEBRAL: secondary cartilaginous joint known as symphysis. This joint is responsible for shock absorption. Hyaline cartilage covers articular surfaces on vertebral bodies and there is a fibrous intervertebral intrarticular disc. The intervertebral disc is made up of a outer layer of a very strong Anulus Fibrosus of concentric lamellae of fibrocartilage and a central droplet of gelatinous material (remnants of the notochord) called the Nucleus pulposus (NP), draws in water, semi-fluid – tense and resilient, but flexible
What happens to the invertebral disc when herniation of the nucleus pulposus occurs
In an adult the NP lies in the posterior part of the disc. Herniation of the NP through the AF is usually posterolateral (because of the central position of the posterior longitudinal ligament), if there is damage to the AF the NP tends to leak out posterolaterally (towards the intervertebral foramen). A herniated disc will press on the roots of a spinal nerve or on the cord itself. The nerve affected are one vertebral level below the disc. If L4 disc herniates, it will press on L5 (and lower) nerves. In the lumbar region the disc is thicker anteriorly.
Describe the anterior and posterior longitudinal ligaments. Make sure to mention their location, function/movements and shape.
Anterior and Posterior Longitudinal are ant. and post. to the vertebral bodies as implied by their names N.B. the posterior ligament is anterior to the spinal cord The anterior longitudinal limits extension. It is a thick, broad band attached to vertebral bodies and discs. It passes from the occipital bone and atlas all the way to the sacrum The posterior longitudinal resists hyper-flexion. It is a narrow band, attached mainly to discs from C2 to the sacrum
Describe the ligamenta flava, supraspinous and interspinous ligaments.
The ligamenta flava limits sudden flexion and support the curvatures. They are strong, elastic bands of varying thickness, between the vertebral laminae. The left and Right may meet and fuse in the midline (Lumbar Puncture). Supraspinous are thick cords between tips of spines From the sacrum to C7, where it continues with the Ligamentum Nuchae. Interspinous ligament links the spinous processes. It is relatively weak and best developed in the lumbar region as the lumbar vertebrae have large spinal processes. It fuses with the supraspinous ligaments
What is the function of ligamentum nunchae? Where is it located?
Limits flexion, provides muscle attachment Broad, fibro-elastic band From external occipital protuberance and posterior edge of foramen magnum, down to C7
What are the ligaments supporting the Atlanto- axial and the Atlanto-occipital Joints? Describe them.
ALAR LIGAMENT: From sides of dens to sides of foramen magnum. Stop xs rotation Superior Longitudinal, Transverse, Inferior Longitudinal are bands of the cruciate Ligament that bind together and prevents xs movement between the axis, atlas and occiput
What is the blood supply of the back?
Arteries form anastomotic rings that arise segmentally from the vertebral arteries and the posterior intercostal and lumbar branches of the aorta Venous plexuses, internal and external coalesce and drain to the veins equivalent to the above arteries. The venous plexuses facilitate tumour spread e.g. prostate gland
What are the superficial muscles of the back mainly for upper limb movement? (HINT: there's 5)
TRAPEZIUS (cowl): skull, ligamentum nuchae and spines of C7 to T12; to scapula and clavicle (laterally) Extends neck, braces (retracts) shoulders, upper fibres elevate (rotate) shoulders in abduction, lower fibres depress LATISSIMUS DORSI: iliac crest, fascia, spines T6 to 12, lower ribs; to humerus. Shoulder extension and adduction LEVATOR SCAPULAE, RHOMBOID MINOR AND MAJOR
The deeper layer, or intrinsic (proper) muscles of the back that keep the vertebral column upright and in extension against gravity. List and describe the superficial group.
Splenius Capitis and Cervicis Ligamentum Nuchae, C and T Spines, to Trans Processes and Skull laterally Together they extend; Alone they rotate and laterally flex
List and describe the intermediate group of intrinsic muscles.
ERECTOR SPINAE 3 columns from lateral to medial From spines and supraspinous ligaments to ribs, trans processes and skull From lateral - medial: Iliocostalis, Longissimus, Spinalis Together – extend; Alone – laterally flex
List and describe the deep group of intrinsic muscles.
Transversospinalis, from trans processes upwards to spines Multiple small muscles in between the spines, in between the trans processes, and from trans processes to ribs Extend, rotate and laterally flex
What are the boundaries of the intervertebral foramen? (superior, inferior, anterior and posterior)
SUPERIORLY = Pedicle and inferior vertebral notch of vertebra above
INFERIORLY = Pedicle and superior vertebral notch of vertebra below
ANTERIORLY = Posterolateral aspect of adjacent vertebral bodies, intervening disc
POSTERIORLY = Anterior aspect of the zygapophyseal joint and capsule
What are the 3 functions of the vertebral column?
Supports body weight
Protects and transmits spinal cord and nerves
What is the public health definition of violence? Why is it a public health problem?
The intentional use of physical force or power, threatened or actual, against oneself, another person, or against a group or community, that either results in or has a high likelihood of resulting in injury, death, psychological harm, maldevelopment or deprivation
Violence affects lives and undermines the physical and psychological health of individuals, families, and communities
Violence, like a range of other environment-and behaviour-related health problems—including HIV/AIDS, cardiovascular diseases, and diabetes — can largely be predicted and prevented
Describe the application of the preventative approach to violence.
PRIMARY (“upfront”) prevention = Focus is on taking action before the risk factors for violence emerge
SECONDARY (“in the thick”) prevention = Involves reacting to the presence of risk factors for violence
TERTIARY (“aftermath”) prevention = Entails reducing the likelihood of the re-occurrence of violence.
SURVEILLANCE – What is the problem: Define the violence problem through systemic data collection
IDENTIFY RISK AND PROTECTIVE FACTORS – What are the causes: Conduct research to find out why violence occurs and who it affects
DEVELOP AND EVALUATE INTERVENTIONS – What works and for whom: Design, implement and evaluate interventions to see what works.
IMPLEMENTATION – Scaling up effective policy and programmes: Scale-up effective and promising interventions and evaluate their impact and cost-effectiveness.
What are the risk and protective factors for violence? Describe them. (HINT: there's 4 categories)
INDIVIDUAL = Victim of child maltreatment, Psychological personality disorder, Alcohol substance abuse, History of violent behaviour
RELATIONSHIP = Poor parenting practice, Marital discord, Violent parental conflict, Low socioeconomic household status, Friends that engage in violence
COMMUNITY = Poverty, High crime levels, High residential mobility, High unemployment, Local illicit drug trade, Situational factors
SOCIETAL = Rapid social change, Gender, social and economic inequalities, Poverty, Weak economic safety nets, Poor rule of law, Cultural norms that support violence
Identify evidence-based initiatives to prevent violence. (HINT: there's 7 points, so mention as many as poss)
1. Developing safe, stable and nurturing relationships between children and their parents and caregivers
2. Developing life skills in children and adolescents
3. Reducing the availability and harmful use of alcohol
4. Reducing access to guns, knives and pesticides
5. Promoting gender equality to prevent violence against women
6.Changing cultural and social norms that support violence
7. Victim identification, care and support programmes.
Discuss the utility of early years’ intervention in prevention. What is a risk factor for future violence?
Inappropriate aggression can develop during the first 24 months following birth:
- Physical aggression is a developmentally appropriate behaviour during early childhood (e.g. play fighting)
- BUT, it needs to be appropriately regulated to ensure the child learns the appropriate alternatives that can be used when necessary.
The early years environment is important for cognitive, language, emotional, and behavioural development. It also lays the foundation for future health.
Child maltreatment is one risk factor for future violence
Define the terms (i) synapse (ii) presynaptic and (iii) postsynaptic.
(i) A junction between two cells where electrical changes in one cell cause a signal to be passed to another usually via a chemical neurotransmitter (some can be electrical synaoses but majority chemical). They primarily occur between neurones but also at the neuro-muscular junction (NMJ). Chemical synapses transmit neuronal action potentials in one direction between cells.
(ii) The neurone before the synaptic cleft responsible for transmitting the NT across the synaptic cleft.
(iii) The neurone after the cleft responsible for receiving and detecting the NT from the synaptic cleft and generating an AP to further the impulse.
Explain the ultrastructural features of chemical synapses, including those in the pre and post synaptic cells.
The terminal of the presynaptic membrane cell forms a swelling called a bouton. Within which there are synaptic vesicles and mitochondria (for providing ATP for active processes). The synaptic vesicles contain NTs which can fuse with the BM (presynaptic membrane) and can release the NT into the synaptic cleft. The neurotransmitter diffuses across the cleft and binds to receptor sites on the post-synaptic membrane generating an AP.
Different neurones can have different resting membrane potentials from -65 to -80 mV depending on their function and hence sensitivity.
How are vesicles recycled and refilled with neurotransmitter in nerve cells?
The endosome is the start of this circular process, enzymes start to pack the NTs into parts of this mass of membrane and budding occurs. These buds nip off becoming vesicles. The loading of the NTs occur here. After budding the vesicles are stored within a protonated structure. The storage doesn’t last long and they become docked. A bouton gives signal for docking, the vesicles have glycoproteins on their coat which allows them to interact with the membrane which causes priming. When Ca+ enter the cell they fuse and exocytosis occurs.
SNARE proteins are used to dock and hold residues so release of NTs is fast when the signal arrives. Synpatobrevin, Syntaxin and SNAP-25 interact forming a helical structure pulling the vesicle down towards pre-synaptic membrane into a primed position. When the Ca+ channel opens and allows Ca+ into the cell, it interacts with the Synaptotagmin molecules which allows the vesicle to fuse with the cell membrane. This allows the emptying of the NTs into the synaptic cleft.
Describe the process of chemical neurotransmission from filling of presynaptic vesicles to neurotransmitter activation and subsequent signalling by receptors.
Small-molecule transmitters and Peptide transmitters - refer to image attached
Post-synaptic membrane: Embedded in the postsynaptic membrane are membrane spanning proteins called receptors. They all belong to either the G protein-linked receptor group (metabotropic receptors), to to the ligand gated ion channel group (ionotropic receptors). The NT is an agonist, designed to bind to the receptor causing it to activate the post-synaptic membrane channel. NTs have a specific shape and charge, the receptor has a complementary shape and charge. Antagonist blocks activation of these ionic channels often by occupying the binding site.
Receptors are sensitive to NTs and the binding of NTs to receptors causes a change in the conformation of these receptors which in most cases open a pore which allows specifically selected ions to travel through (ionotropic). Metabotropic act by a process of a cascade event which causes an ion channel to open or a process in the nucleus of the cell indirectly.
Ionotropic Receptors: When the ligand binds to its binding site, it induces a conformational change in the receptor such that a pore from the inside to the outside of the cell is formed. The pore is characteristic of the receptor type in both size and charge, which means each receptor can be specific to a single or varied number of ions. The passage of ions into and out of the cell changes the voltage of the cell, either to depolarise (net positive charge) the cell or hyperpolarise (net negative charge) the cell. This can work as an inhibitory pathway if it allows hyperpolarisation as the cell becomes more negative.
Metabotropic Receptors: The NT binds to the receptor changing its binding site ever so slightly on the cytosolic side, allowing the G protein to bind to it. This causes a change in conformation of the G protein which changes a GDP for a GTP (binds another phosphate, increasing in energy, becomes charged) and it also “breaks”, one of the three piece molecule is lost and “floats around”. These changes in conformation allow the G protein to interact with the inactive membrane bound enzyme, activating it such that it can produce its own messengers. These messengers bind to the ion channel activating it and allowing movement of ions in and out of the cell. Upon activating the enzyme the G protein complex loses a phosphate (GTP —> GDP) which again changes its conformation allowing it to rebind to the “lost” piece “floating around the cell”. Now it is ready to interact with the receptor again should it receive a NT.
Define (i) Excitatory Post synaptic Potential and (ii) Inhibitory post synaptic potential. Explain these phenomena in the context of summation and integration of information.
Post synaptic potentials (PSPs) are cause by the passage of ions through ion channels which have been opened following receptor/neurotransmitter interactions.
(i) A net flow of positive ions into the cell depolarises the membrane (brings it closer to the threshold) and is thus termed EXCITATORY (EPSP). Single EPSPs rarely result in an action potential.
(ii) Conversely a net flow of negative ions hyperpolarises the cell (further from the threshold) and is termed inhibitory (IPSP)
For both IPSPs and EPSPs the amplitude of the signal decreases with distance.
What are the 4 differences between EPSPs and action potentials?
- EPSPs do not actively propagate along the axon
- No voltage gated current in EPSPs, they are caused by direct or indirect ligand gating
- Na+ and K+ ions flow through the same non ion specific channel
- EPSPs have no refractory period thus a series of EPSPs can summate
Define (i) Spatial summation (ii) Temporal summation. (HINT: think of shovel analogy)
(i) When excitatory potentials from many different presynaptic neurons cause the postsynaptic neuron to reach its threshold and fire.
(ii) When a single presynaptic neuron fires many times in succession, causing the postsynaptic neuron to reach its threshold and fire.
As an analogy, spatial summation is like using many shovels to fill up a hole all at once. Temporal summation is like using a single shovel to fill up a hole over time. Both methods work to fill up the whole (the postsynaptic neuron reaches its action potential threshold).
Give named examples of local anaesthetics and explain their clinical uses.
AMIDE CONTAINING (most commonly used):
Lidocaine (lignocaine) – medium-acting, rapid onset
Prilocaine – medium-acting, no vasodilation
Bupivacaine \ Levobupivacaine – long-acting, slow onset
Articaine – short-acting, rapid onset
ESTER CONTAINING (extremely rarely used):
Tetracaine – long-acting, very slow onset
Chloroprocaine – medium-acting
Benzocaine – atypical mechanism of action
What is the mechanism of action of local anaesthetics?
Local anaesthetics work by reversibly blocking voltage-gated Na+ channels
The structure of a local anaesthetic essentially can be split into three regions. What are these 3 regions? What is each regions function?
aromatic; ester or amide bond; basic amine side-chain
AROMATIC REGION determines the solubility and relative hydrophobicity which is important for its passage through membranes.
ESTER/AMIDE BOND determines the duration of action in the body as it is the part of the molecule that is degraded enzymatically and limits the duration of the drugs. Amide bonds tend to be harder to deal with and are metabolised by the liver. Ester bonds can be metabolised by plasma esterases which are found in the plasma.
BASIC AMINE SIDE-CHAIN allows the molecule to become ionised and act as weak bases. It is hence capable of accepting protons. They don’t completely dissociate in water and is dependent on the pH of the solution it is in. This is important as ionised drugs, which are charged, do not pass easily through membranes. If it is protonated it will not readily and easily pass through membranes.
What isthe structure of a peripheral nerve? What is the order of loss of functions when using LA's?
Consists of fibers of different function, diameter and insulation. All can be blocked by LAs, but at different rates
SKELETAL MUSCLE TONE
The probability that a local anaesthetic will block an impulse relies on 5 factors, what are these factors?
1. Diameter of the fiber
– Smaller nerve fibers are blocked more easily than large fibers
2. Myelination status
– Myelinated fibers blocked more easily than unmyelinated
3. Length of nerve exposed to drug
4. Length of time exposed to drug
5. Concentration of drug
What is the general pKa value range for local anaesthetics?
Between 8 and 9
What is the Henderson Hasselbach eqn for a weak base?
pKa - pH = log10 ( [BH+] / [B] )
Explain the onset and duration of action of local anaesthetics. How can the duration of action be increased? What are the risks invovled in increasing the duration?
Many LAs show use-dependence by binding to open (active) or inactive channels related to the frequency of neuronal firing, fast onset in faster firing neurones.
Duration of action is dictated by rate of removal. Factors for this include; blood flow (can be limited by vasoconstrictive agents such as adrenaline or noradrenaline); action of plasma esterases (ester-linked LAs only) and hydrophobicity of the drug.
To increase the duration of action these things can be manipulated. Most local anaesthetics cause vasodilation (except cocaine which causes vasoconstriction and prilocaine which has no vaso effect) and as the duration of action is dictated by rate of removal, decreased blood flow to an area decreases the rate of removal. This can be caused by use of a vasoconstrictive agent such as adrenaline which can increase duration up to 2X as long. This can also decrease bleeding during surgery but increases the risk of ischaemic damage at extremities.
What are the 6 types of routes of administration of LAs? Give examples for each.
- Nose, mouth, bronchial tree, cornea, urinary tract
- Injection into tissues to reach nerve branches / terminals
3. NERVE BLOCK
- Small or large regional block by injection around nerve
4. INTRAVENOUS REGIONAL
- Double-cuff method to contain LA to a limb
5. EXTRADURAL (epidural - particuarly bupivicane)
- Used in thoracic, lumbar and sacral regions
6. SUBARACHNOID (intrathecal)
- Drug injected into the subarachnoid space (CSF)
What is used to now enhance dermal anaesthesia? Describe said drug.
Eutectic Mixture of Local Anaesthetics (EMLA)
It is a mixture of lignocaine and prilocaine in which the melting point is lower than in the individual chemicals allowing it to be applied as a cream
A higher concentration of both chemicals can be used and there is more chance it will get across the skin
What are the dangers and side effects of local anaesthetics?
Unwanted effects from local anaesthesia are caused by entry into the systemic circulation.
CVS - is excitable tissue congaing voltage gated sodium channels
- Disrhythmias, sudden fall in BP, Effects on the heart and the vasculature
CNS - also excitable tissue
- Restlessness, Tremors, Convulsions, Respiratory centre depression, Death