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Physiology for Anaesthetists > Genetics and Ageing > Flashcards

Genetics and Ageing Flashcards

1
Q

What is a chromosome and how does it differ from chromatin

A

Chromatin is compacted into chromosomes during mitosis and meiosis forming 22 pairs of autosomes and 1 pair of allosomes. Chromatin is made up of compacted DNA wrapped around histone proteins.

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2
Q

Classify the four nucleobases and define how this nucleobases are paired in DNA

A

Pyrimidines (CuT Pie or ‘py’)
Cytosine
Thymine

Purines (Pure gold - ‘Ag’ periodic table)
Adenine
Guanine

Pairing
AT
CG

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3
Q

Define DNA

A

Deoxyribonucleic acid or DNA is a polymer of 4 nucleotides in sequence bound to a complementary DNA strand and folded into a double helix. The strands run antiparallel 5’ to 3’.

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4
Q

Simplify the structure of DNA and differentiate nucleotide from nucleoside from nucleobase

A

Posphate - Pentose Sugar - Nucleobase - hydrogen bond - Nucleobase (complementary) - Pentose sugar - Phosphate.

Sugar phosphate backbone attached to nucleobases.

Nucleobase = CTAG
Nucleoside = nucleobase + Pentose sugar
Nucleotide = nucleobase + Pentose sugar + PO4
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5
Q

Which pathway forms the sugars found in DNA

A

The pentose phosphate pathway

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6
Q

What is RNA

A

The amino acid sequence of protein is encoded by the DNA sequence in the cell nucleus. When the cell needs to synthesize protein, the code is anchored in the cell nucleus, and protein manufacturing apparatus (ER/Golgi) is located within the cytoplasm. RNA is produced as a copy of DNA genetic code in the nucleus and exported to the cytoplasm, where it is used to synthesize protein.

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7
Q

List the differences between RNA and DNA

A

RNA - extra hydroxyl group on sugars (hence ‘deoxy’)
RNA - has Uracil instead of thymine
RNA - single strand - no antiparallel strand to form double helix

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8
Q

What are the 3 types of RNA and what is their function?

A

messenger - mRNA - produced by transcription in nucleus and then transferred to ER for use in protein synthesis

transfer tRNA - 20 types gather 20 aa’s in cytoplasm and transfer to ribosome for protein synthesis

ribosomal rRNA - Aligns tRNA units in their correct positions along the mRNA sequence

The amino acids are joined together and a complete protein released.

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9
Q

Define a codon

A

Triplet of nucleosides that encodes for an individual amino acid - e.g. GCA represents aa alanine

mRNA - codons
tRNA - anticodons
Jigsaw match

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10
Q

Give three examples of errors may occur during DNA replication/repair. Which of these has to most significant effect on changing protein synthesis and why?

A
  1. Point mutation
  2. Deletion
  3. Insertions

Deletions and insertions are the worst because “frame shift’ can occur with the ensuing DNA encoding a significantly different protein

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11
Q

Describe the gene mutation in sickle cell disease and how this mutation leads to the the ‘sickling’ of red blood cells

A

Chromosome 11
Point mutation in the DNA code for the beta chain of Hb
GAG (Glutamic acid) is changed to GTG (Valine)

Glutamic acid - polar
Valine - non-polar

This causes aggregation of Hb and thus shape change of the erythrocyte under conditions of low O2 tension.

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12
Q

Describe the genetic defect in cystic fibrosis and how this manifests clinically

A

Chromosome 7
> 1000 point mutations described of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene –> encodes a transmembrane Cl- channel
Most common is delta F508 mutation
–> deletion of 3 nucleotides (an entire codon which codes for phenylalanine, F) at the 508th position.

Thickened secretions that prevent clearance by ciliated epithelium resulting in blockages of:

  1. Small airways (pneumonia)
  2. Pancreatic ducts (malnutrition)
  3. Vas deferens (incomplete development and infertility)
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13
Q

Describe the genetic defects in Huntingdon’s disease

A

Chromosome 4
Insertion of repeated segments of DNA
Codon for glutamine (CAG) is repeated multiple times within the Huntingdon gene on chromosome 4 = trinucleoside repeat disorder

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14
Q

What is haploid and diploid

A

haploid - cell containing 23 chromosomes (gametes)

diploid - cell containing 46 chromosomes (human cells)

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15
Q

What is an allele

A

A gene that codes for a specific trait e.g.blue alleles and brown eye alleles. (Mendelian).

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16
Q

Give 3 examples of autosomal dominant diseases

A
  1. Hypertrophic cardiomyopathy
  2. Polycystic kidney disease
  3. Myotonic dystrophy
  4. Malignant hyperthermia
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17
Q

Give 3 examples of autosomal recessive diseases

A
  1. Sickle cell disease
  2. Wilson’s disease
  3. Cystic fibrosis
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18
Q

Give 3 examples of X-linked recessive diseases

A
  1. Haemophilia A
  2. Duchenne muscular dystrophy
  3. Red-green colour blindness
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19
Q

Define functional reserve

A

The difference between maximum and basal levels of function - safety margin for trauma/disease/surgery/healing

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20
Q

What are the hypothesized mechanisms of aging

A
  1. Stochastic -> dependent on time and probability - due to random errors in protein synthesis
  2. Non - stochastic -> “biological clock for each species dependent on neuroendocrine or immune mechanisms

Progressive imbalance between oxidative stress and metabolic protection of oxidative stress –> increased ROS –> damaged membranes/proteins/DNA –> decreased antioxidant scavenging capacity –> progressive cycle –> decreased bioenergetic capacity –> loss of functional reserve –> susceptibility to disease and infection –>Increased probability of death

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21
Q

What happens to the heart with age

A
  1. Decreased myocytes
  2. Decreased conduction fibre density
  3. Decreased sinus node number
  4. LV wall thickening
  5. Interstitial fibrosis
Systolic dysfunction (reduced contractility)
Diastolic dysfunction (reduced compliance)
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22
Q

Why is sinus rhythm vital in aged patients

A

Reduced LV compliance –> decreased earl diastolic filling with compensatory increase in late diastolic filling of LV to maintain EDV and SV –> therefore strong reliance on LA filling of LV in the aged.

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23
Q

How does cardiac output change with age

A

An 80 year old has 50% CO at aged 80 (vs CO at 30 yrs)

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24
Q

How is the vasculature affected by age

A

Arteriosclerosis –> AAA/Carotid artery stenosis etc.

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25
Q

How is the autonomic nervous system affected by age?

A

SNS - beta receptors less sensitive –> 2% loss of HR response during dynamic exercise.

PSNS - Reduced vagal tone –> therefore can’t reduce vagal tone below an already reduced baseline.

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26
Q

What happens to elastic recoil of the lungs and chest wall compliance with age –> how does this affect the pressure volume curve

A

Elastic recoil decreases –> increased static compliance
Chest wall compliance decreases

Pressure-volume curve shifts to the left. Lest change in pressure required for same volume change.

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27
Q

What happens to static lung compliance with age?

A

Increases

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28
Q

What happens to dynamic lung compliance with age?

A

Becomes more frequency dependent

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29
Q

How does residual volume change with age

A

Increases by 10% per decade after 50

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30
Q

How is vital capacity changed by increasing age?

A

Decreases

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31
Q

How does closing volume change with age

A

Increases

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32
Q

How does FEV1 change with age and why

A

Chest will stiffens with age - calcification of costo-chondral cartilage/costo-vertebral joints and progressive weakening of the auxiliary musculature of ventilation —> decreased FEV 1 and increased WOB

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33
Q

Describe the changes to the pulmonary vasculature that occur with aging

A

Decreased cross-sectional area of pulmonary capillary bed –> increased PVR –> higher pulmonary artery pressure.

Hypoxic pulmonary vasoconstriction is blunted in the elderly which may cause difficulty with one lung ventilation.

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34
Q

What happens to mean PaO2 with age and why?

A

PaO2 = 102 - (0.498 x Age)

  1. CC encroaches FRC
  2. Closing volume is more –> V/Q mismatch
  3. Deteriorating parenchymal integrity –> decrease surface area –> increased (A - a)dO2.
  4. Decreased sensitivity of respiratory centres to hypoxia and hypercapnoea –> diminshed or delayed response to injury
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35
Q

How is Nervous system effected by aging

A

Reduced functional reserve
Nerves - high O2 utilization –. altered mitochondiral bioenergetics with age compromise reserve –> alters the response to anaesthetic agents and perioperative stress.

Brain weight at 20 yrs = 1400 g
Brain weight at 80 yrs = 1200 g

36
Q

How are the kidneys affected by age

A

Progressive reduction in renal mass

  1. Glomerulosclerosis
  2. Thickening of vascular intima
  3. Fibrosis of stoma
  4. Chronic infiltration by inflammatory cells

RPF decreases more than GFR
FF increases to a state of hyperfiltration (adapatation for loss of functioning glomeruli)

Reduced ability to concentrate urine
Reduced ability to excrete acid load
Sodium loss in the face of adequate sodium intake

37
Q

How is liver function affected by age

A
  1. Decreased hepatic blood flow –> but large reserves
  2. Reduced hepatic drug clearance
  3. Reduced hepatic synthesis of plasma cholinesterase
38
Q

How does body composition change with age

A

Increased abdominal fat mass
Increased obesity
Decreased resting BMR
Decreased energy expenditure (1% per year after 20yrs)

39
Q

How is glucose metabolism affected by age

A

Plasma glucose higher due to glucose intolerance

40
Q

How is the locomotive system affected by age

A

Reduction in height (atrophy of spinal muscles etc. - spinal anaesthesia more difficult)
Osteoporosis –> positioning patient in theatre.

41
Q

Which plasma protein binds acidic drugs and how is it affected by age. Which plasma protein binds basic drugs and how is it affected by age?

A

Acidic drugs –> Albumin –> decreases with age –> Increase free fraction

Basic drugs –> alpha 1 - acid glycoprotein –> increases with age –> decrease free fraction

42
Q

How does body composition change with age and how does this affect

A

Decreased lean body mass
Increase body fat
Decrease in total body water

EFFECT

  1. Smaller central compartment with increased serum concentrations after bolus administration
  2. Increased Vd –> prolonged effect
43
Q

Do elderly patients need more or less volatile and why

A 
MAC falls by 6% per decade
1. Decreased cell density
2. Lower Cerebral O2 consumption
3. Lower CBF
Alterations in ion channels/synaptic activity or receptor sensitivity
44
Q

Does age directly affect the duration of neuraxial anaesthesia

A

No

45
Q

Define elderly

A

> 65 years

46
Q

By how much does perioperative mortality increase per decade after 65 years of age

A

35% per decade

47
Q

What are the two theories of aging

A

Extrinsic (Stochastic = random)
- cellular damage / ROS / Radiation / Errors protein synthesis

Intrinsic
- Pre-programmed genetically determined process

Whatever the underlying cause, the process occurs at very different rates between individuals and between organ systems within an individual

48
Q

What is the ultimate effect of aging

A

Reduced functional reserve of organ systems with a threat to homeostasis in the face of stress.

49
Q

Summarise the change in body composition in the elderly

A

Decreased % lean body mass from

  1. Cell loss in solid organs
  2. Decrease body water
  3. Loss of muscle mass
  4. loss of bone mass
  5. Loss of skin an SC tissue

Body fate % increases, with a shift in distribution from peripheral to visceral sites

50
Q

Why do the elderly develop isolated systolic hypertension and what haemodynamic effects result from this

A

After 40 years:

  • Collagen accumulates whilst elastin production falls
  • Collagen also accumulates damage over time with stiff, non-enzymatic cross-linking between fibers.
  • Connective tissue thus stiffens in the arteries, veins and the myocardium

Haemoodynamic effects

  1. Isolated systolic hypertension
  2. Widened pulse pressure (reduced diastolic pressure too)
  3. Increased afterload (Aorta cannot accommodate SV)
  4. LVH (increased afterload)
  5. Reduced LV compliance with diastolic dysfunction
  6. Increased dependence on atrial contraction due to diastolic dysfunction
  7. Reduced DBP –> compromise coronary perfusion
51
Q

How do SV, HR and LVEF vary in the elderly vs younger individuals at rest

A

Actually unchanged

However, there is reduced beta-adrenergic sensitivity and reduced cell numbers in the SA node

Reduced maximum heart rate (SA cells down)
Reduced contractility (myocyte numbers down)
---> Result in reduction in maximum CO in response to exercise or stress
52
Q

Describe the pattern of decline of maximum cardiac output in the elderly

A

Maximum cardiac output declines by 1% per year after 50.

So by 80 years –> Max CO is 30% less than at 50 years.

53
Q

How is the conducting system of the heart affected by age

A

Fibrosis in the conducting system may cause conduction abnormalities

54
Q

Summarise the changes in the blood vessels in the elderly

A
  1. Reduced elastin and increased damaged + stiff collagen (stiffer arterial walls even in the absence of atherosclerosis)
  2. Intimal thickening
  3. Media calcification
  4. Endothelial dysfunction (less NO)

Venous stiffening –> impairs venous capacitance and ability to maintain stable preload

55
Q

Summarise the changes to autonomic tone in the elderly

A

Increased SNS tone
Reduced PSNS tone
Diminished baroreceptor responses

56
Q

Summarise the changes to respiratory mechanics in the elderly

A
  1. Reduced chest wall compliance
    - Calcification costal cartilage
    - Arthritis costovertebral joints
    - Stiffness intercostal muscles
    - Reduction height thoracic spine (osteoporosis)
  2. Reduced respiratory muscle mass
    - Intercostals and diaphragm weaker

Overall –> Increased WORK of breathing
- Breathing rapid and shallow

  1. Lung parenchyma
    - Loss elastic tissue –> dilatation/enlargement airways + increased alveolar size + fusion adjacent alveoli –>reduction in alveolar surface area and a decrease in surface tension inward recoil
57
Q

How do the physiological changes associated with aging affect lung function tests?

A
  1. RV - increase 5% - 10% per decade
  2. FRC - increase 1 - 3 % per decade
  3. Closing capacity increase –> airway closure –> V:Q mismatch during tidal ventilation
  4. TLC - unchanged
  5. VC - Reduced as RV increased
  6. FEV1 - falls by 25 ml/year after age 20
  7. FVC - falls by 20 ml/year after 20
  8. FEV1 : FVC ratio therefore falls
  9. Diffusing capacity - decreased due to thickened alv-capillary barrier
58
Q

Why does arterial oxygenation decrease with age

A
  1. Decrease diffusing capacity (thickened alv-cap barrier)
  2. Reduced alveolar surface area –> V:Q mismatch
  3. Small airways close prematurely (Increased closing capacity)
  4. Increased shunting of blood due to alveolar destruction
59
Q

Give one formula to predict PaO2 in the elderly

A

Predicted PaO2 = 13.3 - (Age/30) kPa

60
Q

How does age affect the respiratory response to hypercapnoea and hypoxia

A

There is a 50% decrease in the response to hypercapnoea and hypoxia

61
Q

What are the airway considerations in the elderly

A
  1. No teeth
  2. Collapsed cheeks - difficult BVM
  3. Cervical spondylosis - reduced ROM
  4. Pharyngeal muscle weakness (POPC + OSA + aspiration risk)
62
Q

Why is the risk of post-operative pulmonary complications increased in the elderly

A

The physiological changes with ageing result in a significant increase in the required work of breathing

63
Q

Summarise the anatomical changes in the kidneys that occur with age

A

Kidneys enlarge until 50 years
25% of their mass then lost over 30 years
- Cortical tissue lost –> glomerulosclerosis
- Acellular obliteration of glomeruli with vascular shunts forming around the lost units

64
Q

How does renal blood flow change with age?

A

RBF decreases 10% per decade
Increased proportion of blood flow to the medulla (GS)

Intrarenal blood vessels show the same changes seen in the blood vessels in the rest of the body with age

65
Q

Why does GFR decline with age. Why can Creatinine be decreased despite this

A
  1. Glomerulosclerosis
  2. Thickened basement membrane

Reduced creatinine production (loss of muscle mass)

66
Q

Which formula should be used to calculate GFR

A

CKD-EPI formula

67
Q

What is tubular senescence

A

With age comes reduced tubular length, interstitial fibrosis and basement membrane changes resulting in disruption of tubular function

  • -> Impaired ability to reabsorb sodium
  • -> Impaired ability to excrete K and H

Reduced ability to regulate electrolytes

68
Q

How is the renal response to aldosterone and ADH affected by age?

A

Renin production is reduced –> reduced response to aldosterone

Response to ADH is reduced

Reduced ability to regulate fluid

69
Q

Why are elderly patients more susceptible to dehydration

A

Decreased thirst response

70
Q

How do elderly patients excrete drugs differently from younger patietns

A

Reduced capacity to clear drugs by the renal route and are more susceptible to injury for nephrotoxic agents

71
Q

What happens to the volume and weight of the brain after age 40. why does this occur? And where do the losses predominate. Which area of the brain is mostly affected by this

A

It decreases by 5% per decade after age 40

  • cell loss
  • decrease dendritic density

Losses more pronounced in white matter vs. grey matter. Not uniformly distributed throughout the brain.

Most affected: prefrontal cortex

72
Q

What changes occur with regard to neurotransmitters and nerve conduction in the elderly

A

Reduced

  • Dopamine
  • Serotonin
  • Brain derived neurotrophic factor

Increased
- Monoamine levels –> free radical release

SLOWING of nerve conduction in the PNS and CNS

73
Q

What happens to the blood brain barrier with age

A

Permeability increases possibly leading to increased neuroinflammation and inapprpriate modulation of CNS function

74
Q

Describe the vascular changes in the brain in the elderly

A
  1. Same as everywhere else
  2. Capillary density decreases
  3. Microvessel deformities increase
  4. CMRO2 and CBF decrease with age
75
Q

Discuss the observable neurological deficits often present in the elderly

A
  1. Cognitive impairment (memory loss)
  2. Auditory impairment
  3. Visual impairment
  4. Decreased mechanoreceptor and proprioceptor density increases risk of falls

Post operative delirium is common in the elderly

76
Q

How is autonomic function altered in the elderly

A

It is decreased.

  1. Impaired thermoregulation (shivering, VC
  2. Reduced beat to beat variation in response to postural changes
  3. Reduced baroreceptor reflex sensitivity
77
Q

What are the requirements for analgaesics and anaesthetics in the elderly population

A

The requirements are diminished

78
Q

Summarise the age related changes in the GIT

A

Oesophagus
- Decrease contraction amplitude and number. Increased number of disordered contractions

Stomach

  • Slowed gastric emptying
  • Atrophic gastric mucosa –> decreased acid and IF production
  • Reduced gastrin secretion

Pancreas
- Normal exocrine function

Small and large bowel
- minimal (polyps / diverticuli)

79
Q

How is Hepatic function affected by age

A

Liver mass and hepatic flow decrease by 20 - 40%.

Decline in phase 1 drug metabolism (loss of endoplasmic reticulum)

80
Q

How does age affect the sex hormones

A

Decreased secretion from endocrine glands and diminished tissue responsiveness to hormones.

E.g. Menopause

  • bone loss
  • Loss of oestrogen cardioprotective effects

E.g. Testosterone levels decline with age (?significance)

81
Q

How does age effect thyroid

A

E.g. Thyroid levels decreased (?clinical effects)

82
Q

How does age effect parathyroid

A

E.g. Parathyroid levels increased (–> osteoporosis)

83
Q

How does age effect GH and ILGF-1

A

E.g. GH and ILGF-1 decreased

- loss of lean body mass and increased % body fat)

84
Q

How does age effect Insulin

A

E.g. Insulin

  • Decreased and insulin resistance (abdominal fat)
  • glucose intolerance
85
Q

How are circadian rhythms affected in the elderly

A

Shifted –>Cortisol release earlier in the day

86
Q

How are secretion and levels of adrenalin and noradrenalin affected in the elderly. why is this important in the perioperative period

A

Baseline levels are elevated

but secretion in response to stress is diminished

NB as inability to regulate temp/HR/CO/BP in the face of surgical stress

87
Q

how is immune function affected by age

A

Immune function declines with age

  • Impaired T cell mediated immunity
  • Increased susceptibility to infection
  • T-cell response to IL-2 diminished
  • Blunted increase in NK cells to infection

Markers of SIRS are elevated in the elderly
- IL6 / TNF alpha / CD 11b/ CD 18 expression

Physiology for Anaesthetists (61 decks)

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