PBL Topic 3 Case 6 Flashcards
What is a diffusion potential?
- The potential difference between the inside and outside of the membrane
What is the Nernst potential?
- The diffusion level that exactly opposes the net diffusion of a particular ion through a memrbane
What is the role of the sodium potassium pump?
- Moves 3Na+ to the outside of the cell
- For every 2K+ to the inside of the cell
- In order to restore the resting membrane potential
What are leak channels and how do they differ in permeability to different ions?
- Channels through which ions leak
- Greater leakage of potassium because it is more permeable
What is the value of the resting potential in large nerve fibres?
- -90 millivolts
- Meaning the potential inside is 90 millivolts more negative than the potential in the extracellular fluid
Explain why the Nernst potential for sodium and potassium differs
- Potassium Nernst potential is -94 millivolts because there is a high ratio of potassium ions inside to outside
- Sodium Nernst potential is +61 because there is a lower ratio of sodium ions inside to outside
What is the resting stage of an action potential?
- Membrane is polarised due to -90 millivolts generated by sodium potassium pump
What is the depolarisation stage of an action potential?
- Membrane becomes permeable to sodium
- Large number of sodium ions diffuse into axon
- Overshoot caused by excess of sodium entering
What is the repolarisation stage of an action potential?
- Sodium channels close
- Potassium channels open
- Rapid diffusion of potassium out
Identify the two types of gating
- Voltage gating involving opening of a protein channel as a result of changing potential
- Chemical ligand gating involving opening of a protein channel due to binding of a ligand e.g. ACh
Describe the gates of a voltage gated sodium channels
- Activation M gate opens when membrane potential becomes less negative than the resting potential
- Inactivation H gate closes as a result of same increase in voltage but it closes slower
What is meant by threshold for stimulation and what is its value?
- Membrane potential becomes less negative than resting potential
- To around -65 millivolts
- Which causes explosive development of an action potential
Explain the process behind the propagation of an action potential
- Excited portion of nerve fibre causes local circuit of current flow to adjacent resting membrane areas
- Positive electrical charges are carried by inward diffusion sodium ions
- Increasing threshold in adjacent areas above threshold for stimulation
What is meant by the all or nothing principle?
- Action potential only occurs if sufficient voltage to stimulate the next area of the membrane builds up
- Above the threshold
- Or it does not travel at all
What is the importance of ATP in nerve impulse?
- Sodium potassium pump re-establishes sodium and potassium concentration differences
- Which requires ATP
What is the ratio of myelinated to unmyelinated nerve fibres?
- 1:2
What is the velocity of conduction in a small unmyelinated nerve fibre compared to a large myelinated fibre?
- Small unmyelinated: 0.25m/sec
- Large myelinated: 1m/sec
Describe the structure of a myelinated nerve fibre
- Central core is the axon filled with axoplasm
- Surrounded by a myelin sheath
Outline the process of myelination
- Membrane of Schwann cell envelops the axon
- Schwann cell rotates around axon many times
- Depositing many layers of sphingomyelin
- Which is an insulator that decreases ion flow through the membrane
What is saltatory conduction?
- Junction between Schwann cells is known as node of Ranvier
- Nerve impulse jumps between nodes of Ranvier
- Increasing the velocity of transmission
What is primary demyelination?
- Myelin sheath is destroyed
- Axons remains intact
What is secondary demyelination?
- Damage to axon
- Resulting in breakdown of of myelin
What happens to the debris of myelin breakdown?
- Phagocytosed by macrophages
- Transformed into droplets of neutral lipids (cholesterol esters)
What is an acute sub-threshold potential?
- Weak negative stimulus incapable of exciting a nerve fibre
What is an acute local potential?
- Excitation takes place in response to voltage increase
- However it is not great enough to pass the threshold level
- Therefore an action potential does not occur
What is an absolute refractory period and why does it occur?
- Period during a which a second action potential cannot be elicited even with a strong stimulus
- Because sodium channels become inactivated
What is a relative refractory period?
- Period during which nerve fibre is more difficult to excite
- But can be excited by a very strong signal
What is a membrane stabilising factor. How does lidocaine act as a stabilising factor?
- Factor that decreases excitability
- Lidocaine acts on activation gate of sodium channels making it more difficult for it to open
Explain how chemical synapses work
- Presynaptic cell releases neurotransmitter
- That acts on postsynaptic receptor proteins
Explain how electrical synapses work
- Direct open fluid channels
- That conduct electricity from one cell to next
- Usually through gap junctions
How does transmission of impulses differ between chemical and electrical synapses?
- Chemical synapses: One way transmission
- Electrical synapses: Signals are transmitted in either direction
What is the importance of one way transmission?
- Specific transmission of signals to discrete and highly focuses areas in the CNS and PNS
- Allows the nervous system to perform its myriad functions
- Including sensation, motor control, memory and many others.
Describe how neurotransmitters are stored and released from the presynaptic terminal
- Stored in transmitter vesicles
- Mitochondria provides ATP for synthesising new transmitter substance
- Action potential spreads over presynaptic terminal
- Depolarisation of membrane causes release of vesicles into synaptic cleft
What are SNARE proteins?
- Proteins that dock vesicles in active zone of presynaptic terminal
-
Identify two types of SNARE protein
- V-SNARES: Synaptobrevin, Synaptotagmins, found on vesicular membrane
- T-SNARES: Syntax, Snap-25, found at nerve terminal membrane
Outline the role of calcium ions in neurotransmitter release
- Binds to another vesicle protein, synaptotagmins
- Triggering conformational change in SNARE complex
- Leading to membrane fusion and neurotransmitter release into the cleft
Identify two types of postsynaptic receptors that neurotransmitters bind to
- Ionotropic receptors: ion channels
- Metabotropic receptors: G-protein second messenger system
What are cation and anion channels?
- Opened as a result of activation of ionotropic / metabotropic receptors in response to neurotransmitters
- Cation channels allow entry of sodium, but block entry of chloride due to lining of negative charges
- Anion channels allow entry of potassium, but block entry of sodium due to small size
What is an excitatory postsynaptic potential (EPSP)?
- Electrical response at an excitatory cation channel
What is an inhibitory postsynaptic potential (IPSP)?
- Hyperpolarisation at an inhibitory anion channel
Outline the molecular and membrane mechanisms used at excitatory receptors
- Opening of sodium channels, influx of sodium ions
- Decrease influx of chloride ions and efflux of potassium ions
- Changes in internal metabolism to excite cell activity
Outline the molecular and membrane mechanisms used at inhibitory receptors
- Opening of chloride channels, influx of chloride ions
- Increased efflux of potassium ions
- Activation of receptor enzymes that inhibit metabolic functions
Outline the process of presynaptic inhibition
- Release of GABA by presynaptic cell
- Which opens presynaptic anion channels
- Allowing influx of chloride into presynaptic cell
- Inhibiting synaptic transmission
What is spatial summation?
- Effect of triggering an action potential in a neuron from one or more presynaptic neurons.
- This occurs when more than one excitatory postsynaptic potential (EPSP) originates simultaneously and a different part of the neurone
What is temporal summation?
- High frequency of action potentials in the presynaptic neuron elicits postsynaptic potentials that summate with each other
What is the role of small molecular neurotransmitters?
- Acute responses of nervous system e.g. sensory signals to brain and motor signals to muscle
What is the role of neuropeptide transmitters?
- More prolonged actions such as long-term changes in numbers of neuronal receptors, long term opening and closure of certain ion channels
How are small molecular neurotransmitters synthesised?
- In cytosol of presynaptic terminal by active transport into transmitter vesicles in the terminal
How are neuropeptides produced?
- Ribosomes as integral parts of large protein molecules
- Which is then enzymatically split from the protein by the Golgi apparatus
- Transported to tips of nerve fibres by axonal steaming
What is Multiple Sclerosis?
- Autoimmune T-cell mediated inflammatory disorder
- Formation of plaques of demyelination throughout the brain and spinal cord
- Occurring sporadically over years (dissemination in time and space)
Outline the epidemiology of MS
- Prevalence of 1.2/1000
- Women outnumber men 2:1
- Typically affects people between 20 and 40 years
- More common in white populations with increasing distance from the equator
Outline 4 environmental causes of MS
- Epstein-Barr Virus (EBV)
- Human Herpes Virus 6 (HHV-6)
- Low levels of vitamin D
- Lack of sunlight
Outline the pathology of MS
- T-cells cross the BBB
- They recognised myelin derived antigens on microglia and undergo clonal proliferation
- Resulting in inflammatory cascade and cytokine release initiating destruction of oligodendrocyte-myelin unit
- Impaired impulse propagation
- Progressive axonal loss
Outline the three types of MS
- Relapsing-remitting, symptoms occurring in attacks over days, and then recovery over weeks
- Secondary progressive, late stage symptoms with gradually worsening disability caused by axonal loss
- Primary progressive, late stage symptoms with gradually worsening disability without relapses or remissions
Outline 3 clinical features of multiple sclerosis
- Optic neuritis caused by demyelination of optic nerve
- Diplopia, vertigo, facial numbness, weakness caused by brainstem demyelination
- Paraparesis with possible Lhermitte’s sign caused by spinal cord lesions in cervical or thoracic cord
Outline the investigations and diagnosis of MS
- Clinical history of neurological symptoms
- MRI demonstrates demyelination
- CSF examination shows lymphocytic pleocytosis and oligoclonal bands of IgG
What is the Clinically Isolated Syndrome?
- Diagnosis of MS cannot be made on first episode of neurological symptoms
- Though an abnormal brain MRI confers a high chance of developing MS
What is treatment for acute relapses of MS?
- Methylprednisolone
How does B-interferon work?
- Inhibits T cell activation
- Preventing T cell proliferation
- Blocks T-cell migration across the BBB
How does glatiramer acetate work?
- Competitive inhibitor of MHC-II
- Since it has a similar structure to myelin basic protein
How does oral fingolimod work?
- Sphingosine-1-phosphate receptor
- That prevents T cells leaving lymph nodes
How does natalizumab work?
- Alpha-4 integrin vascular adhesion molecule
- Preventing lymphocytes entering the CNS
How does alemtuzumab work?
- Anti-CD52 molecule
- Responsible for lymphocyte depletion
What is the prognosis of MS?
- Life expectancy reduced by 7 years on average
Outline the mechanism of action of methylprednisolone
- Binds to intracellular glucocorticoid receptors
- Which dimerises then enters the nucleus
- Which binds to glucocorticoid response element and upregulates transcription
Outline the immunosuppressive and anti-inflammatory properties of glucocorticoids such as methylprednisolone
- Reduced activation of neutrophils, macrophages, mast cells
- Reduced activation of T-helper cells, reduced clonal proliferation of T-cells
- Decreased production of prostanoids owing to decreased COX-2 expression
- Decreased generation of cytokines
- Increased synthesis of inflammatory factors such as IL-2 and annexin 1
Outline 4 adverse effects of glucocorticoids
- Poor response to infection or injury, poor wound healing
- Oral candidiasis
- Peptic ulceration
Describe the biosynthesis of serotonin
- Tryptophan is converted into 5-hydroxytryptophan by tryptophan hydroxylase
- 5-hydroxytryptophan is converted to 5-hydroxytryptamine by an amino acid decarboxylase
How is serotonin degraded?
- Monoamine oxidase
- Which converts it to 5-hydroxindole acetaldehyde
- Which is then dehydrogenated and excreted in the urine
Where in the body are the highest concentrations of serotonin found?
- Enterochromaffin cells of the gut regulating peristalsis and motility
- Platelets, causing platelet aggregation
- CNS where it excites and inhibits neurons
- In sensory nerve endings to stimulate nociceptive nerve endings
Where are serotonergic cell bodies found and how do the nuclei project to other regions of the brain?
- Raphe nuclei of the pons and upper medulla
- Via the median forebrain bundle
What type of receptors are serotonin receptors? What is the exception?
- All are G-protein coupled
- Except for 5-HT3 which is a ligand gated cationic channel
What are 5-HT1 receptors?
- Somatodendritic autoreceptors in the raphe nuclei
- Major target for drugs used to treat anxiety and depression
Outline the four physiological functions that relate to 5-HT pathways
- Hallucinatory effects
- Sleep, wakefulness and mood
- Feeding behaviour
- Pain pathways
Describe the biosynthesis of noradrenaline
- L-tyrosine is converted to dopa by tyrosine hydroxylase
- Dopa is converted to dopamine by dopa decarboxylase
- Dopamine is converted to noradrenaline by dopamine beta-hydroxylase
Which protein is involved with transport of noradrenaline into vesicles. What is stored in vesicles containing noradrenaline?
- Reserpine-sensitive Vesicular Monoamine Transporter (VMAT)
- ATP
- Chromogranin
- DBH
Which receptor is responsible for noradrenaline reuptake?
- Noradrenaline (NET) transporter
Where are noradrenergic cell bodies found and how do the nuclei project to other regions of the brain?
- Locus coeruleus located in the pons
- Via the median forebrain bundle
What type of receptors are adrenoreceptors?
- G-protein coupled receptors
Identify 3 functions of alpha-1 receptors
- Motor control
- Condition
- Fear
Identify 3 functions of alpha-2 receptors
- Blood pressure control
- Sedation
- Analgesia
What are beta-1 receptors?
- Found in cortex, striatum and hippocampus
- Involved in long-term effects of antidepressant
What are beta-2 receptors?
- Found in cerebellum
- Involved in long-term effects of antidepressant drugs
Outline the physical features of depression
- Insomnia or hypersomnia
- Poor appetite and weight loss
- Increased appetite and weight gain
- Loss of libido and erectile dysfunction
Outline the emotional features of depression
- Feelings of unworthiness
- Worrying
- Suicidal thoughts
- Delusions of guilt
- Feelings of futility
- Hypochondriacal preoccupations
Outline the epidemiology of depression
- 5% prevalence
- More common in women
- No increase with age, difference by ethnic group of socio-economic class
What is dysthymia?
- Mild or moderate depressive illness
- Intermittently over 2 years
- Characterised by tiredness and low mood
What is seasonal affective disorder?
- Recurrent episodes of depressive illness
- Occurring in the winter months in the northern hemisphere
- Can be treated with bright light therapy
Identify three types of puerperal affective disorder
- Maternity blues, brief episode of tearfulness that occurs in the majority of women and resolves spontaneously
- Postnatal depressive disorders, lack of emotional bonding and poor relationship with partner
- Postpartum psychosis, attempts to kill the child or suicide
Outline two differential diagnoses for depression?
- Alcohol misuse
- Thyroid disease
Outline two investigations for depression
- Clinical history to rule out alcohol misuse
- Less commonly used T4 or TSH measurements
Outline the pathogenesis of depression
- Deficit of noradrenaline and 5-HT and BDNF
- Elevated levels of glutamate and action of NMDA receptors
- Stress leads to increased cortisol release
- All of which result in a detrimental gene transcription response and neural apoptosis
Outline the genetic component of depression
- Polygenic
- Polymorphisms include serotonin transport genes
- Short/short allele implicated in greatest risk. long/long allele implicated in lowest risk
Outline environmental factors that predispose a person to depression
- Physical, sexual and emotional abuse or neglect in childhood
- Serious life events, including divorce in women and unemployment in men
Outline two examples of SSRI
- Fluoxetine, sertraline
Outline two examples of TCAs
- Amitriptyline, nortriptyline
Outline an example of an SNRI
- Venlafaxine
Outline an example of an NRI
- Bupropion
Outline two examples irreversible, non-selective MAOIs
- Phenelzine, tranylcypromine
Outline three examples example of MRA
- Mirtazapine, trazodone, mainserin
Outline the effects of acute administration of SSRIs
- Increased levels of 5-HT results in increased activation of 5-HT1a receptors
- Which reduce 5-HT release
Outline the effects of prologued administration of SSRIs
- Elevated levels of 5-HT desensitise 5-HT1a receptors
- Which increases 5-HT release
How can alpha-2 adrenoreceptor antagonism enhance 5-HT release?
- Block of a2 autoreceptors on noradrenergic nerve terminals innervating cell bodies of 5-HT containing neurons in dorsal raphe
- Enhanced noradrenaline release will activate excitatory postsynaptic a1 receptors on 5-HT neurons
- Increasing firing and thus release of 5-HT
How is sertraline administered and what is the dosage?
- Taken orally 50mg daily
- Increased in steps of 50mg weekly
- To a maximum of 200mg
Outline three common side effects of sertraline
- Nausea
- Anorexia
- Insomnia
- Loss of libido and anorgasmia
Outline three uncommon side effects of sertraline
- Serotonin syndrome when combined with MOI characterised by tremor, hyperthermia, and cardiovascular collapse
- Risk of bleeding associated with inhibition of 5-HT reuptake by platelets
- Discontinuity syndrome marked by shivering, anxiety and dizziness
How is venlafaxine administered and what is the dosage?
- Orally
- Taken 75mg daily in 2 divided doses
- To a maximum of 375mg daily
Outline 4 side effects of venlafaxine
- Antimuscarinic effects such as dry mouth, blurred vision, constipation and urinary retention
- Cardiovascular effects such as postural hypotension
- Weight gain
- Sedation
Outline two roles of monoamine oxidase
- Within nerve terminals it regulates intraneuronal concentration of NA and 5-HT
- Inactivation of endogenous amines such as tyramine
What is the cheese reaction?
- Tyramine is normally metabolised by NAO so little reaches circulation
- MAO inhibition results in acute hypertension, severe throbbing headache and rarely intracranial haemorrhage
What is ECT?
- Used in severe life-threatening depression
- Performed under general anaesthetic, involves passage of current over scalp to induce epileptic fit
- Given twice a week for 3-6 weeks
- Free of serious side effects
What is CBT?
- Identification of automatic thoughts about self, situation and future
- Including catastrophising, overgeneralising, categorical thinking
- Identifying links between thoughts, behaviour and mood
- Testing logic of said thoughts e.g. Socratic questioning
Outline the mechanism of action of nortriptyline and amitriptyline
- Inhibition of noradrenaline (physical symptoms), 5-HT (emotional symptoms) and dopamine uptake (less so)
- By competition for the binding site of the nerve terminal
Identify 3 side effects of nortriptyline and amitriptyline
- Antimuscarinic effects e.g. dry mouth, blurred vision, constipation and urinary retention
- Cardiovascular effects e.g. postural hypotension and QT prolongation
- Weight gain
- Sedation
Identify another use of TCAs aside from antidepressants and outline how they work
- Neuropathic pain
- Preventing noradrenaline reuptake
- Which inhibits transmission of nociception
Outline the mechanism of action of mirtazapine
- Blocks a2 adrenoceptors
- Blocks 5-HT2C receptors
- Enhancing noradrenaline and 5-HT release
Outline the mechanism of action of trazodone
- Blocks 5-HT2A and 5-HT2C receptors
- Enhancing 5-HT release
Outline the mechanism of action of mainserin and explain why it is no longer used
- Blocks a1 adrenoreceptors
- Blocks 5-HT2a receptors
- Blocks H1 receptors
- Causes bone marrow depression
Give an example of a selective, MAO-A specific inhibitor and an advantage of this type of drug over phenelzine and tranylcypromine
- Moclobemide
- Cheese reaction and drug reactions are much less severe
What is meant by coping?
- The process of managing stressors
- That have been appraised as taxing or exceeding a person’s resources
What is meant by primary appraisal?
- Assessing the potential threat of the external stressor
What is meant by secondary appraisal?
- Assessing the effectiveness of options to manage the situation and the person’s internal responses
Identify 5 goals of coping
- Reduce stressful conditions
- Adjust or tolerate negative effects
- Positive self image
- Emotional equilibrium
- Maintain relationships
What is meant by approach coping and what type of stressor is it more suitable for?
- Confronting problem and taking direct action
- Long-term stressor
What is meant by avoidance coping?
- Minimising the importance of the event
- Short term stressor
Identify two types of approach coping
- Problem focused
- Emotional focused
Identify two examples of emotional-focused coping
- Behavioural strategies e.g. talking to friends about the emotions
- Cognitive strategies e.g. thinking about a problem in a positive way
Which type of problem evokes problem focused coping?
- Work related
Which type of problem evokes emotional focused coping?
- Health
- Relationships
How does coping strategy differ between ages?
- Children and middle-aged people use problem focused coping
- Teens and elderly people use emotional focused coping
How does coping strategies differ between men and women?
- Men tend to use problem focused
- Women tend to use emotional focused
How does controllability affect coping strategies?
- If the individual believes the condition is controllable they are more likely to use problem-focused coping
- If the individual does not believe the condition is controllable they are more likely to use emotion-focused coping
What does the ‘ways of coping’ checklist measure?
- Different coping styles
Identify two effects coping should have
- Reduce intensity and duration of stressor
- Reduce likelihood that stress will lead to illness
Which type of coping is associated with better outcomes?
- Approach, problem-solving coping
Outline Leventhal’s self regulatory model
- Illness is dealt with in the same way as any other problem
- Individuals try to maintain status quo in three stages
- Interpretation of problem
- Coping strategy
- Appraisal
Identify four causes of help-seeking behaviour
- Interpersonal crisis
- Interference with social and work life
- Sanctioning (family and friends encouraging help-seeking)
- Temporising (putting a time limit on symptoms)
Identify two reasons for not demonstrating help-seeking behaviour
- Fear of embarrassment
- Fear of the condition
What is the purpose of the Mental Capacity Act?
- Protect people who cannot make decisions for themselves or lack the capacity to do so
Who does the Mental Capacity Act apply to?
- Severe mental health condition
- Severe learning disability
- Brian injury
- Stroke
- State of unconsciousness
Identify five key principles of the Mental Capacity Act
- Person assumed to have capacity unless established otherwise
- Person not to be treated as unable to make a decision unless all steps to help them do so are unsuccessful
- Person not to be treated as unable to make a decision because they make an unwise decision
- Act or decision must be in their best interests.
- Regard must be had to whether the outcome can be as effectively achieved in a way that is less restrictive of the person’s rights and freedom of action
What is meant by advanced decision?
- A decision made by a person
- After they have reached the age of 18 and have the capacity to do so
- Regarding specified treatment (or lack of) when they eventually lack capacity
When does an advanced decision have full legal force?
- In writing
- Signed by patient or by a person in patient’s presence
- With a signature fo a witness
When is an advanced decision invalid?
- If patient does something inconsistent with advanced decision
What is Lasting Power of Attorney?
- Legal document allowing a person who is at least 21
- To appoint a person to make decisions on their behalf should they lose capacity one day
- Personal welfare or property and affairs matters
Outline the NICE guidelines for depression
- Mild depression: Psychological intervention e.g. CBT
- Moderate - severe depression: Stepwise treatment:
- (1) SSRI (sertraline)
- (2) SNRI (venlafaxine) / MRA (mirtazapine) >
- (3) Antipsychotic (quetiapine) / lithium
- (4) TCA (nortriptyline)
- (5) MAOI (phenelzine)
