Systems 2 - Integrated Physiology Flashcards
Equivalents
= moles x valence
So 1 mol Na⁺ = 1 eq/L
1 mol Ca²⁺ = 2 eq/L
Moles are unit of quantity, 6 x 10²³
PaCO₂
PaCO₂ (arterial) = Rate of CO₂ production / alveolar ventilation rate
Quantity of moles
1 mole =
10³ mmol
10⁶ μmol
10⁹ nmol
pH equations
pH = -log[H⁺]
So minor changes in pH -> major changes in [H⁺]
pH = pk + log[A⁻]/[HA]
Importance of pH in body
- enzyme activity/protein strucure affected
- Ca²⁺ ions - 50% are free in blood, ionised, to stabilise nerve and muscle membranes. 50% are bound to albumin, which competes with H⁺ for binding. -> when decreased H⁺, less free Ca²⁺, so less of a membrane stabilising effect
- –> so in hyperventilation, increased pH, hyperexcitable nerves
Trousseau sign, Chvostek’s sign
Trousseau - hand cramped forward, claw
Chvostek - muscle twitch when tap facial nerve
-> indicate disturbance of plasma calcium, or acid/base balance disruption
Buffers
Resist a change in pH by absorbing or releasing H⁺ when an acid or base is added
pH will still change slightly - buffer pair is weak acid and its conjugate base
pk
= the pH where an acid is 50% dissociated, [A⁻]/[HA] = 1
Lower pk -> stronger acid
Extracellular buffers
Bicarbonate
Haemoglobin
Phosphate
Plasma proteins
-> work together to resist change, isohydric principle
Bicarbonate buffer system
pk = 6.1 CO₂ + H₂O = H₂CO₃ = H⁺ + HCO₃⁻
BUT rarely know [H₂CO₃], so use solubility coefficient of 0.03 - [H₂CO₃] = 0.03 x PCO₂
- > pH ∝ [HCO₃⁻]/PaCO₂
- > pH depends on the ratio of bicarbonate to carbon dioxide
IMPORTANT
- high conc of buffer pair in plasma
- PaCO₂ regulated by respiratory system
- [HCO₃⁻] regulated by kidney
Acid production in body
Body is net producer of acid
Kreb’s cycle makes CO₂
Metabolism makes H⁺
Gut below pylorus -> HCO₃⁻ to lumen in alkaline tide, H⁺ into blood
Renal handling of bicarbonate
Reabsorption - of bicarbonate ions by glomerular filtration. If too high, exceeds tubular threshold and spills into urine
Regeneration - of bicarbonate lost in buffering, by secreting protons into nephron to be trapped and excreted by non-bicarbonate buffers, and by secreting ammonium
-aemia
Acidaemia - acidic blood, pH less than 7.35
Alkalaemia - alkaline blood, pH more than 7.45
-osis
Acidosis/alkalosis - processes that cause a change in pH of blood
Usually -> -aemia
‘osis-without-aemia’ when pH in normal range
Compensation
Attempts to return pH to normal
Pathological chronic change in PCO₂ or HCO₃⁻ is compensated by homeostatic change in the other
Renal compensation (adjusting HCO₃⁻) is more effective than respiratory compensation (adjusting CO₂) but takes longer to get effect, days
-> if renal and lung disease, big problem
Change in same direction, if increase in HCO₃⁻, body will increase CO₂ to compensate
Normal range of pH, PCO₂, HCO₃⁻
pH - 7.35-7.45
PCO₂ - 35-45
HCO₃⁻ - 21-29
Alkalaemia
pH > 7.45
HCO₃⁻ raised, metabolic alkalosis
PCO₂ decreased, respiratory alkalosis
Acidaemia
pH < 7.45
HCO₃⁻ decreased, metabolic acidosis
PCO₂ raised, respiratory acidosis
Acid base map
Electroneutrality
Total [cations] = total [anions] in body fluids, can’t have net charge
Anion gap in -ve ions, unsure where from
Normally 8-16mEq/L
Other anions are Cl⁻ and HCO₃⁻
Hyperchloraemic metabolic acidosis with normal anion gap
As cations have increased, to fill in gap, Cl⁻ increases
Anion gap remains unchanged
Caused by too much bicarb out
Increased anion gap metabolic acidosis
As bicarbonate has decreased, to fill in gap, anion gap increasases
Cl⁻ remains unchanged
Caused by too much acid in
Causes of increased anion gap metabolic acidosis
- more fixed acid production, eg lactic acidosis/ketoacidosis
- ingestion of fixed acids, eg aspirin
- inability to excrete fixed acids, eg in renal failure
Causes of hyperchloraemic metabolic acidosis with normal anion gap
- loss of bicarb from gut, eg diarrhoea, ileostomy
- loss of bicarb via kidney, eg renal tubular acidosis
Causes of metabolic alkalosis
SALINE RESPONSIVE
- vomiting, diuretic use, volume contraction
- treated with saline to decrease RAAS activity
SALINE UNRESPONSIVE
- primary hyperaldosteronism
Causes of respiratory alkalosis
Decreased PCO₂, caused by:
- mechanical ventilation, hyperventilation
- stimulation of respiratory centre
Causes of respiratory acidosis
Increased PCO₂, caused by ALVEOLAR HYPOVENTILATION
- defects in neuromuscular chain
- work of breathing exceeds the strength of respiratory pump, eg in obstruction to airflow, restrictive lung diseases, decreased lung compliance, so increased CO₂ production
Constant body temperature
Homeotherms (birds and mammals) have physiological mechanisms to regulate temperature
- allows them to inhabit physiological niches
- enzyme reactions work in narrow range so good to keep constant
Humans do vary by location in body in order to preserve core temperature (isotherms areas of equal heat), and also varies with time
BMR
Basal metabolic rate
- without doing anything, we produce heat, ~100W
Clinical measurement of body temperature
Must be a representative site (into core)
Must be easily accessible
External auditory meatus most common now
Major routes for heat gain and loss equation
Metabolism - Evaporation ± Conduction ± Convection ± Radiation = 0, when heat gain = heat loss
20% loss by evaporation
40% loss by radiation
40% loss by convection
Thermoreceptors
SKIN (peripheral)
- specific
- sensitive to dynamic and absolute changes
- small receptive fields
- more cold receptors than warm
CENTRAL (posterior hypothalamus)
- more warm receptors than cold
- also in midbrain, medulla, spinal cord
Central controller of temperature
Posterior hypothalamus
Set point generated here
ACh main transmitter
Increase Na⁺, increase set point, increase body temp
Increase Ca²⁺, decrease set point
Peripheral and central input are integrated to fine tune response (eg in cool temps, there must be a greater core temp increase to stimulate sweating)
Adaptation/acclimatisation to heat
Lower sweating threshold
Increased sweat rate
Decreased electrolyte content of sweat
Behavioural changes
Adaptation/acclimatisation to cold
Decreased skin blood flow
Decreased shiver threshold
Thyroid hormones
Behavioural changes
Pyrexia
= fever
Above 38 degrees is significant
Infection -> toxins -> WBC reaction -> pyrogens (IL family) -> increased set point in hypothalamus –> shivering, vasoconstriction, pyloerection -> increase in core temperature
Temperature regulation in the newborn
Can’t shiver, will develop at a few months old
And small size, so large SA:volume ratio, lose heat easily
- > brown adipose tissue instead, on scapulae and around major arteries
- abundant mitochondria here, for uncoupled oxidative phosphorylation
Ageing
= maturation and deterioration
Maturation dominant until around 30
Maximum survival roughly constant, so intrinsic as well as extrinsic factors
Senescence = post-reproductive decline in viability, accompanying biological age
Causes of ageing
Free radicals
Apoptosis
Genetics
Causes of ageing - free radicals
Occur in normal chemical reactions
Normally involve molecular oxygen, making OH. and O₂.
Production increased by environmental agents - UV, gamma, Xrays -MAINLY SMOKING
-> lipid peroxidation - breakdown products react with DNA -> mutations -> impaired protein function
Enzymes can control:
- superoxide dismutase, catalase
- vitamins C and E are antioxidants, trap free radicals
Causes of ageing - apoptosis
Shrinkage, degrade nuclear DNA, breakdown mitochondria, break down cell, phagocytosis
Useful in development, eg tissue remodelling
In ageing - neurons, cardiac tissue, cells of immune system all die
Causes of ageing - genetics
DNA redundancy failure
- non-error sequences will eventually be exhausted, so errors will be expressed
Failure in chromosome replication
- telomeres shorten with each division, if small enough cell will die
- evidenced by progeria/Werner’s syndrome - genetic condition -> accelerated ageing
Homeostasis and ageing
Corrections to normal take longer to occur in older people
- eg blood glucose, recovery from exertion, temperature acclimatisation
- > physiological effectiveness reduced
Structural cardiovascular changes in ageing
HEART
Fewer cardiac myocytes - necrosis and apoptosis
Increased collagen, so stiffer
VASCULATURE
Arteries - more collagen and smooth muscle, less elastic tissue, collagen cross linked, calcium deposited (so stiffer) -> increased afterload on left ventricle
Veins - fibrosis, intima thickening, loss of elastic tissues, so -> varicosities under high pressure
Functional cardiovascular changes in ageing
- Reduced maximum heart rate, and reduced stroke volume -> so reduced cardiac output
- Increased bp, as stiffness in arteries increases resistance
- Baroreflex sensitivity reduced, so postural hypotension
Renal changes in ageing
Decrease in kidney mass with age, loss of nephron units
Reduced glomerular filtration rate
Fewer glomerular capillary loops, change in vascular tone
-> respiratory adjustments needed to maintain pH, impaired ability by kidney to restore buffer systems
Thermoregulation and age
Reduced metabolic rate
Reduced muscle mass
Increased adipose tissue
Reduced activity
-> so less heat generated by metabolism
Also
- less evaporation loss (sweat glands atrophy)
- more radiation loss (less thermal insulation, thinner skin and subcutaneous fat)
- less convection/conduction loss (reduced skin blood flow to compensate for reduced cardiac output)
- > so elderly are less able to cope with hot/cold challenges, though core temperature should not change
- sweat later, and shiver later than would in young (though once established can do)
Ideal temperature not changed, just precision lost
Hypoxia vs hypoxaemia
Hypoxia - low tissue O₂ content
Hypoxaemia - low O₂ in blood
PᴀO₂ = alveolar pressure PaO₂ = arterial pressure
Types of hypoxia
Hypoxaemic - ventilatory defect, alveolar diffusion problems
Anaemic - reduced O₂ carriage in blood
Stagnant - cardiovascular shock, shunts
Toxic - reduced extraction of O₂ by tissues
Symptoms of hypoxia
- dyspnoea (SOB), laboured breathing
- fatigue, lethargy
- confusion
- tachycardia
- deterioration of vision
- headaches
- peripheral cyanosis
- euphoria, moodiness, dizziness
- pins and needles
- > loss of consciousness
Ventilatory response to hypoxaemia
Gaseous exchange stops at PᴀO₂ of 40
Hypoxaemia -> hyperventilation
PᴀO₂ declines at a disproportionate rate, but more breathing also decreases CO₂ though, so more space for O₂ if CO₂ reduced
- carotid bodies monitor PaO₂ (innervated by glossopharyngeal nerve), and direct to hyperventilate when gets too low
Limit to hyperventilation
Can’t cope with very low PaO₂
- as blood-brain barrier is permeable to CO₂ - as PaCO₂ decreases, CO₂ also decreases in CSF
- > respiratory alkalosis, rise in pH
- central chemoreceptor on medulla will inhibit drive to hyperventilation
- contradicts with peripheral chemoreceptor (carotid bodies) drive
-> therefore hyperventilatory response not as high as should be
Few days later, renal compensation will kick in, decreasing HCO₃⁻ to maintain pH another way - ACCLIMATISATION
Cardiovascular response to hypoxia
Transient rise in cardiac output
Heart rate and stroke volume then decrease
-> can’t adapt well
Long term, better
- increased capillarity to muscles
- reduced muscle fibre diameter, so reduced O₂ diffusion distance
- increased myoglobin content of muscle
Immediate response to hypoxia
(seconds)
Increased ventilation
Pulmonary vasoconstriction
Tachycardia, increase in systemic bp
Intermediate response to hypoxia
(days)
Increased ventilation, though with CSF compensation
Renal compensation of respiratory alkalosis, HCO₃⁻ elimination
O₂ dissociation curve shifts to right, reduced HbO₂ affinity, so easier to offload O₂
Increased urine loss
Long term response to hypoxia
(weeks-months)
Polycythaemia - more RBCs, high haematocrit
Increased muscle capillarity
Increased muscle myoglobin/rate of anaerobic metabolism
Tissue hypoxia -> erythropoiesis
Increased expression of hypoxia-inducible factor (HIF-1)
- stimulates production of erythropoietin by kidney
- increases liver production of transferrin
- increases absorption of iron from intestine by regulation of hepatic mediators
-> more haemoglobin, more RBCs (BUT, increases blood viscosity, raised afterload on heart)
Increased urinary output at high altitude
Reduced aldosterone, so urine loss
- > risk of significant dehydration
- blood volume may allow circulation to accomodate increase in RBCs -
Acute mountain sickness symptoms
- headache + one of:
- dizziness
- fatigue
- sleep disturbance
- GI disturbance
Rarely progresses to pulmonary and cerebral oedema
Acute mountain sickness treatment
DESCENT
Oxygen therapy
Hyperventilation
Acetazolamide
High altitude pulmonary oedema
- potentially fatal
- around 3 days after ascent
- hypoxaemia
- > pulmonary vasoconstriction
- pulmonary pressures increase to maintain cardiac output
- > transudation of fluid into alveoli
Symptoms - dyspnoea, fatigue, persistent dry cough (with pink frothy sputem)
High altitude cerebral oedema
- potentially fatal
- even more dangerous but very rare
- around 3 days after ascent
- hypoxaemia
- > cerebral vasoconstriction
- cerebral pressures increase to maintain cardiac output
- > transudation of fluid onto brain tissue
Same symptoms as acute mountain sickness, + ataxia, altered consciousness/mental status, retinal haemmorhage
Stress response
Physiological changes that occur in response to stressors such as trauma, surgery, burns and sepsis, to aid survival and eventual repair
- signalled via afferent neuronal impulses from site of injury, and release of cytokines by macrophages and monocytes in damaged tissues
Acute phase stress response
IL6 produced by macrophages
- > fever
- > increased granulocytes, especially neutrophils and platelets
- > liver increases production of proteins by CRP (which adheres to bacteria and promotes complement activation and phagocytosis)
Full blood count
To identify cause of infection
TOTAL WHITE CELL COUNT
Neutrophils raised -> bacterial infection
Lymphocytes raised -> viral infection
Eosinophils raised -> parasitic infection/allergy
CRP test
To monitor degree of inflammation
Measure CRP sequentially to see trend
Behavioural changes in stress response
As brain stimulated by neuronal and cytokine signals
INCREASED
- arousal
- aggression
- defence
- vigilance
DECREASED
- sexual activity
- feeding
Fight or flight response in stress response
Adrenaline released
-> α adrenoreceptor
- relaxation of smooth muscle in GI tract
- mydriasis (pupil dilation)
- constriction of arterioles in skin and kidney
(- hepatic gluconeogenesis and glycogenolysis)
-> β adrenoreceptor
- relaxation of smooth muscle in GI tract
- increase heart rate and contractility
- bronchodilation
- relaxation of detrusor in bladder
- dilation of arterioles in skeletal muscle
(- hepatic gluconeogenesis and glycogenolysis, lipolysis in adipose tissue, renin secretion in kidneys)
-> so blood diverted to skeletal muscle, away from gut and skin (-> glucose production, salt retention, raised bp)
HPA axis activity in stress response
Hypothalmic-Pituitary-Adrenal axis
Increases activity
So hypothalamus releases CRH - corticotrophin releasing hormone
To anterior pituitary, which releases ACTH - adrenocorticotrophic hormone
To adrenal gland, which releases CORTISOL (will inhibit sequence now)
Cortisol effects
- increased gluconeogenesis
- increased protein catabolism
- increased lipolysis
- > survival during fasting
- decreased immune response
- decreased inflammatory response (steroids use!)
- increased vascular response to catecholamines, as increases α1 adrenoreceptors
- decreased histamine release from mast cells
- > treats anaphylactic shock
Adrenocortical insufficiency
Primary - addison’s disease
Secondary - secondary to exogenous steroid therapy
Salt and water metabolism in stress
SALT
Sympathetic stimulation of kidney
-> RAAS activation, Na⁺ retention
WATER
ADH release from posterior pituitary
-> water retention by distal nephron
-> so post op (stress), dangerous to give hypotonic solutions, as retain lots of fluid -> hyponatraemia, cerebral oedema, death
Insulin
For glucose -> glycogen in liver, -> fat in adipose, -> protein in muscle
Increases glucose uptake into cells, and reduces blood glucose
Metabolic changes to provide fuels in stress
- protein catabolism
- stimulated by cytokines and cortisol
- > amino acids for gluconeogenesis in liver
- gluconeogenesis and glycogenolysis
- > glucose and ketone bodies as fuel for heart and brain
- lipolysis
- stimulated by cortisol, catecholamines, insulin deficiency
- > free fatty acids and glycerol to liver
Hyperglycaemia
As catecholamines and cortisol stimulate hepatic glycogenolysis and gluconeogenesis
So increased glucose in blood
Decreased insulin production, insulin resistance (very high insulin concs reduce wound healing and increase infection)
Systemic Inflammatory Response Syndrome (SIRS)
Will become sepsis -> severe sepsis -> septic shock
Triggered by surgery, trauma, infections, burns, haemmorhagic shock
Stress response a destructive force?
Intensive care uses drugs and machines to try to restore physiological values to normal
- may not be good; high insulin always associated with death, increased fluids following traumatic haemmorhage give death
-> so consider different therapeutic end points
Na⁺/K⁺ levels
More Na⁺ extracellularly (blood tastes salty!)
More K⁺ intracellularly
