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BAB > Week 11 > Flashcards

Week 11 Flashcards

1
Q

Macroscopic brain ages

A

Ventricular enlargement, cortical thinning, decreased post mortem weight, the accumulation of white matter hyperintensities

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2
Q

Cellular changes ageing

A

Synaptic pruning, axonal loss, mitochondrial changes, alterations glial cell numbers

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3
Q

Molecular changes ageing

A

Altered gene expression, disrupted calcium signalling, epigenetic changes

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4
Q

Clinically ageing brain

A

Cognitive decline (information processing speed, memory, reasoning, and executive function)
Decreased well being
Increased symptoms low mood
Increase neurodegenerative disease

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5
Q

Changes in brain as we age

A

Volume decline 5% per decade from 40 years
Neuronal volume loss not number
Prefrontal cortex most affected
Hippocampus, striatum, temporal lobes, cerebellum
Don’t tend to get changes in brain stem or primary visual cortex

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6
Q

Changes in cell types in brain as we age

A

Neuronal cell, stable no. Reduced volume
Oligodendrocyte, increases
Astrocytes stable
Microglia increased. Inflammatory phenotype, senescent MHCII but primed

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7
Q

Microglia

A

Phagocytes: clear debris such as beta amyloid and damage to myelin
Release growth factors and neurotrophins such as BDNF
Trigger repair by astrocyte stimulation and stem cell recruitment
Activated in inflammation, in response produce inflammatory cytokines which help bring in Th1 helper cells
Damage to astrocytes or damage to synapses will also activate microglial cells
Once they do their jobs they go back to being quiescent

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8
Q

Microglial senescence

A

Changes in microglia distribution: increase in numbers/density in neural parenchyma. Decreases regularity in distribution, translocation into ares not previously occupied by microglial (outer layers by retina)
Changes in microglial morphology: decreases in individual ramification (dendritic arbor area, branching and total process length). Appearance of morphological changes suggestive of increased activation state (eg perinuclear cytoplasmic hypertrophy, retraction of processes) sporadic appearance of dystrophic microglial in aged human brains
Changes in microglial dynamic behaviour: decrease in rate of process movement, decrease in rate of migration to focal tissue injury

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9
Q

How does ageing microglial affect function at synapses

A

At the presynaptic neurone the mitochondria dont function as well with age
They produce less ATP so there’s less energy to get nT out presynaptic neurone
Changes in gene expression of transporters in presynaptic neurones
Post synaptic neurone: get changes in number and affinity of post synaptic neurone receptors and changes in calcium homeostasis- normally important for triggering AP

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10
Q

Changes in neurotransmitters with age

A

Dopamine: 10% decrease per decade from 20, frontal cortex to striatum affected, Parkinsonism
Serotonin and BDNF changes
ACh: reduction enzyme CAT (greater in hippocampus) which converts precursors Ach to ACh so less ach in neurone less in synaptic cleft. Reduction M1, M2 receptors, loss cells produce ach, Alzheimer’s disease
GABA: reduced GAD enzyme produces GABA and reduced GABA receptors. Huntingtons disease

Mitochondrial dysfunction, ROS, calcium dysregulation

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11
Q

Memory and parts of the brain

A

Semantic: medial temporal lobe (incl hippocampus) and cortex
Episodic: medial temporal lobe (incl hippocampus and cortex)
Procedural: cerebellum, striatum, putamen tend not to change with age
Emotional: amygdala
Working

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12
Q

Different areas more affected lead to different clinical features

A

Prefrontal cortex firstly and most affected by age
See changes in hippocampus, striatum, temporal love, cerebellum
Don’t tend to get changes in brainstem or primary visual cortex
Working memory may reduce with age- perceptual speed
Verbal ability associated with long term memory- stays fairly constant with age

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13
Q

Brain predicted age

A

Brain PAD: brain predicted age difference
Positive brain PAD ‘older appearing brain’
Negative brain PAD ‘younger’ appearing brain
Brain PAD predicts survival over 8 years so good marker of physiological age as opposed to chronological age

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14
Q

Alzheimer’s take home messages

A

Alzheimer’s disease is the most significant disease in an ageing population and as yet there are no pharmacological treatments to modify or prevent the disease
Amyloid hypothesis describes accumulation beta amyloid Ab as the event that triggers AD
Ab is a derivative of the larger amyloid precursor protein APP. The roles of a, B and gamma secretase play an essential part in this model

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15
Q

Intellectual failure type

A

Mild cognitive impairment: when people have cognitive defect but not dementia doesn’t get in the way everyday life
Dementia: cognitive development gets in the way of everyday functioning
Delirium: common in developing brains and ageing brains, sudden change in someone’s intellect (cognition) and their arousal usually due to infection

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16
Q

Intellectual failure broad presentation

A

Forgetful not usual self
Acuteness of symptoms is key affect on everyday function

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17
Q

Intellectual failure intervention

A

Diagnosis: dementia often underdiagnosed
By diagnosing offer support
Non pharmacological support
Pharmacological support: cholinesterase inhibitors increase Ach in synaptic cleft

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18
Q

Dementia

A

Chronic syndrome
Impairs cognition not just memory global impairment
Affects everyday function
Causes: Alzheimer’s, vascular disease, lewy body dementia, frontal-temporal dementia, posterior cortical atrophy (pratchett)
Intervention: diagnosis, drugs, support
Rise in UK ageing population

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19
Q

Amyloid cascade hypothesis

A

Missense mutations in APP, PS1, PS2 genes
Increased Ab42 production and accumulation
Ab42 oligomerisaiton and deposition as diffuse plaques
Oligomers weaken communication and plasticity at synapses which could be what stops brain forming and retrieving memories
Ab leads to ROS production that damages neurons changes in excitotoxicity of cell
Astrocytes and microglial activated (complement factors, cytokines etc)
Progressive synaptic and neuritic injury
Altered neuronal ionic homeostasis; oxidative injury
Altered kinase/phosphatase activities- tangles
Widespread neuronal/neuritic dysfunction and cell death with transmitter deficits
Dementia

20
Q

Another key feature is neurodegeneration

A

Neuronal death and damage is triggered by Ab but some of its affects are mediated by another protein called tau
In health neurone molecules are carried along axon on series of tracts made of microtubules and stabilised by tau protein
In Alzheimer’s tau in modified causing it to dissociate from microtubules and adopt an abnormal shape and it move from axon to cell body
These remains stick together and deposit
Eventually these process kill neurone
Also misfolded tau proteins spread across synapses into healthy neurones where they make healthy tau proteins misfold spreading pathology across Brain

21
Q

Forms of AD

A

Dominantly inherited forms AD: Missense mutations in APP or PS1or PS2 genes -> increased relative Ab42 production throughout life
Non dominant forms AD: includes sporadic AD. Failure of Ab clearance mechanisms (ApoE4 inheritance , faulty Ab degradation etc)-> gradually rising AB42 levels in brain

22
Q

risk factors through the life course: modifiable and non modifiable

A

Risk factors for dementia- lots occur throughout life course
65% risk developing dementia related to things cant change non modifiable
35% potentially modifiable
Early life: less education
Midlife: hearing loss, hypertension, obesity
Late life: smoking, depression, physical inactivity, social isolation, diabetes

23
Q

Basic principles of anaesthesia

A

“Triad of general anaesthesia”
-need for unconsciousness
-need for analgesia
-need for muscle relaxation (loss of reflexes)
Work by depression CNS activity

24
Q

Structure of inhalational anaesthetics

A

Simple unreactive compounds
Short chain molecules
No one chemical class

25
Q

Mechanism of anaesthetic action; the lipid theory Meyer 1899

A

Concentration of agents required to immobilise tadpoles is inversely proportional to lipid:water partition coefficient
Hydrophobicity/ lipid solubility is important

26
Q

The lipid theory

A

Subsequent observations:
[anaesthetic] in cell membrane 0.05mM-> anaesthesia for any agent
Anaesthesia occurs when volume of lipid expanded by 0.4%
High pressure reverses the anaesthesia as it reverse the membrane expansion
Agents act by ‘volume expansion’ of the lipid cell membrane
Or increase fluidity of cell membrane
Interference with conduction of nerve impulses

27
Q

The protein theory

A

Perhaps lipid solubility is merely required for access to proteins (ion channels, receptors)
The Meyer correlation can be mimicked by binding to certain enzymes/proteins
‘Cut off’ phenomenon anaesthetic potency for homologous series of long chain anaesthetic compounds: increase chain length-> increases lipid solubility -> increase anaesthetic potency up to a point
Beyond a certain chain length potency stops but lipid solubility still continues
Stereoselectivity of anaesthetic potency preserved with protein binding
Stereoisomers have same lipid solubility but GA potency if different

28
Q

General anaesthetics effect

A

Binding to hydrophobic pockets on proteins to have their effect found in cell membrane which is why lipid solubility is important for access
If molecules too big cant access binding site so no anaesthetic effect
Multiple different proteins which individual anaesthetics bind to- contributes to GA affect

29
Q

Molecular targets for general anaesthetics (inhaled/gaseous agents)

A

Ion channels but no single target
GABA a receptor (ligand gated channel)-> enhance GABA affect increase inhibition
K+channel activation decrease membrane excitability
Excitatory ligand gated channels:
NMDA receptor (glutamate), 5-HT3, ACh nicotinic
Inhibitor ligand gated channel: glycine
Binding to these targets produces CNS depression

30
Q

Concentration dependent effects of general anaesthetics

A

When increase anaesthetic
Ability to form memory is first thing inhibited
Then lose consciousness
Increase more-> analgesia
Lot more to suppress movement
Increasing effect on CV and Resp system—> death overdose
GA have a narrow therapeutic window. Clinical dose is dose required to suppress movement in 2-3 x that dose=overdose

31
Q

Stages of anaesthesia

A

Analgesia: drowsiness, reflexes intact, still conscious
Delirium (the induction phase): excitement, delirium, incoherent speech, loss consciousness, unresponsive to non painful stimuli. Muscle rigidity, spasmodic movements, cardiac arrhythmias, vomiting, choking- dangerous phase
Surgical anaesthesia: unresponsive to painful stimuli, breathing regular, abolition of reflexes, muscle relaxation, synchronised electoencephalohgraph EEG
Medullary paralysis- overdose: pupillary dilation, respiration/circulaiotn ceases, EEG wanes death

32
Q

What makes a good anaesthetic agent

A

Potent and fast acting

33
Q

MAC: a measure of anaesthetic potency in man

A

Minimal alveolar concentration
-the concentration of anaesthetic in the alveoli required to produce immobility in 50% patients when exposed to noxious stimulus
(Patients height, weight and sex all variables)
Expressed as % of inspired air %v/v
MAC inversely proportional to lipid solubility the more soluble in oil/lipid the lower the [anaesthetic] in patients inspired air %v/v required to produce anaesthesia
Assumed at equilibrium that inspired conc= alveolar conc= Brain conc
Lipid solubility oil:gas partition coefficient is main determinant of anaesthetic potentcy

34
Q

Pharmacokinetic aspects of inhalation anaesthetics

A

Rapid induction and recovery are important properties of an anaesthetic allows control over depth of anaesthesia
Main factors influencing rate of induction:
-properties of anaesthetic
-physiological factors

35
Q

Access of anaesthetics to brain
Equilibration between different compartments

A

Inhaled anaesthetic dissolves in blood blood:gas partition coefficient
Goes to Brain where it has its effect tissue:blood partition coefficient

36
Q

Access of anaesthetics to brain
Transfer to alveoli

A

Increase [anaesthetic] increases rate and depth of breathing increases speed of induction

37
Q

Access of anaesthetics to brain
Transfer to blood

A

The higher the solubility of gas means blood has large capacity for that agent so more molecules required to saturate the blood decreases speed induction
Blood needs to be saturated before increase [anaesthetic] in brain
If you have agent relatively insoluble in blood then less required to saturate the blood and transfer to brain much faster increases speed of induction
Lower blood:gas partition coefficient increases speed of induction
Blood:gas partition coefficient inversely proportional to speed of induction THIS IS THE MAIN FACTOR
Factor 2: rate of pulmonary blood flow, higher cardiac output higher rate pulmonary blood flow faster transfer of agent into blood stream

38
Q

Access of anaesthetics to brain
Transfer from blood to tissue

A

Solubility in tissue
The tissue:blood partition coefficient for all anaesthetics =1 in lean tissue (Braingrey matter, muscle)
So [anaesthetic] in brain rises fast
Solubility in adipose tissue tissue:blood partition coefficient»1 in adipose tissue so has high capacity for agent. So if individual has lots adipose tissue decrease speed of induction as most GA doesn’t reach brain most end up in adipose tissue
Tissue blood flow: high flow in lean tissue->fast transfer so fast transfer GA to brain. Low rate blood flow in adipose tissue so slower transfer

39
Q

Elimination of inhalation anaesthetics

A

Mainly via lung: dependent on factors involved in speed of induction in reverse
Metabolism not important for anaesthetics: isoflurane 0.2% is metabolised, N2O 0.04%
Exceptions: methoxyflurane ~50%is metabolised, halothane ~20% metabolised possibility of toxicity in liver

40
Q

Halothane

A

Adv: potent fairly fast
Dis: poss liver toxicity

41
Q

Enflurane

A

Adv: less liver damage
Dis: poss seizures

42
Q

Isoflurane

A

Advs: rapidly acting, muscle relaxation
Dis: bad smell

43
Q

Sevoflurane

A

Adv: pleasant odor, rapid recovery
Dis: metabolites -> renal damage

44
Q

Nitrous oxide 1:1 O2 Entonox

A

Advs: very rapid, good analgesic
Dis: low potency, normally combined with other agents

45
Q

Balanced anaesthesia

A

Using combination of different drugs for optimal clinical effect with lowest risk

46
Q

Intravenous anaesthetics

A

Rapid onset
Short acting
Commonly used for induction
Can be used alone for short procedures
Mechanism of action through interaction with specific ligand gated receptors:
-potentiation of GABAa receptor action: thiopental (barbiturate), etomidate, propofol, midazolam (benzodiazepine)
-antagonism NMDA receptors: ketamine “dissociative anaesthetic” lasts 10-20minsm rapid onset,-> sensory loss, analgesia, paralysis, surgical anaesthesia but no loss consciousness

47
Q

Adjuncts to general anaesthetics

A

Premedication: given before to decrease anxiety, pain, induce amnesia w/o loss consciousness
-benzodiazepines: sedation, anxiolysis, amnesia,eg lorazepam, midazolam
-opioids (pain relief): eg morphine, fentanyl, pethidine
-antimuscarinics to facilitate intubation and ventilation eg atropine, hyoscine, glycopyronium
Muscle relaxants: to relax deep abdominal, tracheal and diaphragm muscles without need for deeper analgesia less likely to overdose
-benzodiazepines
-neuromuscular blockers: eg tubocurarine, pancuronium, gallamine, suxamethonium
Anti-emetics: decrease perioperative nausea when recovering analgesia:
-metoclopramide

BAB (10 decks)

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