SEM 2 SBA Flashcards
RAAS
-low ECF volume so slow flow through tubule –> more time for reabsorption or decrease in renal perfusion (BP)
-decrease in GFR
-low [Na+] at macula densa
-sympathetic stimulation
-renin released from juxtaglomerular cells
-renin converts angiotensinogen (produced by liver) to
Ang I
-Ang I -> Ang II by ACE (on endothelium of lung vessels)
-Ang II binds to (AT1 receptor - Gq) :
On vascular SM :
-vasoconstriction
-increasing TPR + BP
On adrenal glands :
-stimulates aldosterone release from zona glomerulosa
-aldosterone increases Na+ reabsorption
-water follows with it by osmosis
-increases blood volume –> decreases Na+ in urine
Macula densa
Region of contact between afferent arteriole + distal tubule of same nephron
Juxtaglomerular (granular) cells
Modified SM cells along afferent arteriole
Renin secreting
Mechano-sensors - detect BP + blood volume
Effect of ANP on renal?
- causes natriuresis (increased Na+ excretion)
- water follows –> diuresis (increased water excretion)
Effect of ANP on vasculature
- causes vasodilatation of vessels
- stimulates G pathway
- stimulates Guanulate Cyclase (GC)
- produces cGMP from GMP
- cGMP activates PKG
- PKG causes vasodilation
- decrease TPR + BP
Effect of ANP on horomes
- acts on kidney to decrease renin release
- reduces Ang II
- reduces vascular tone
- ANP reduces aldosterone release
- ANP inhibits renin release
- reducing Ang II + aldosterone
- it inhibits aldosterone directly
- reduces ADH release
- to decrease Na + reabsorption
- to decrease water uptake
- decreases collecting duct permeability
- excrete more Na+, decrease blood volume + BP
- opposes RAAS
Pressure natriuresis
- increase renal arterial pressure
- forcing more Na+ excretion
- vasoconstriction
- decreases flow
- increases pressure drop so Pc constant
- renal arterial auto-regulation
- increase in medullary capillary pressure
- afferent arteriole, glomerulus, efferent arteriole leads to peritubular capillaries
- higher pressure in peritubular capillaries
- plasma moves into interstitial space
- rise in pressure in interstitial area
- reduces reabsorption of Na+ from tubule
How to excrete Na+?
Cardiac natriuretic peptides (ANP)
Pressure natriuresis
PCT
- Active re-absorption of NaCl (65%), AA, glucose
- Passive re-absorption of K+, HCO3-
- Secretion of NH3, drugs
LOH
- Asecending is H2O impermeable but active re-absorption via Na+/ K+/ 2Cl-
- Descending is H2O permeable –> salty medulla but low permeability to ions
DCT
- Regulates pH by absorbing HCO3- + secreting H+ into filtrate
- Aldosterone increases absorption of Na+ and Cl-
Collecting ducts
- Absorption of Na+ and urea from filtrate
- ADH increases absorption of H2O by inserting aquaporins2
ADH
-binds to V2 receptor on basolateral membrane
-Gs activates AC intracellular pathway
-increase cAMP
-increase PKA
-ADH causes translocation of vesicles to luminal membrane where aquaporins are inserted
-water flow down osmotic gradient into conc interstitial
tissue (thus blood)
Countercurrent flow
=tubular fluid moves down in descending limb + moving up in other
-on thick ascending limb pumping NaCl out of tubular fluid into interstitial fluid between 2 limbs
-impermeable to water so no water out ascending
-solutes build up in interstitium as you move down
-at bottom intersitium very hyperosmotic
-hyperosmotic gradient
-fluid enters into descending
-fluid osmolality same as plasma (300)
-as it moves down, water leave due to hyperosmotic interstitium pulling water out
-water moves out
-tubular fluid becomes hyperosmotic
-fluid moves down descending becoming more
hyperosmotic.
-fluid moves up
-water trapped as impermeable to water
-osmolality of tubular fluid –> hypoosmotic
-when tubular fluid leaves LoH it’s hypoosmotic (diluter
than plasma)
Effect of Na+ not being removed?
Wherever Na+ goes water will follow so
- decreased Na+ removal
- reduces ECF volume
- decreases blood volume
- decreased CO
- decreased BP + oedema
Uses of loop diuretics eg Frusemide?
Chronic heart failure - low ECF volume, CVP, CO
Acute pulmonary oedema - venodilatation
Acute renal failure - increased renal blood flow
Thiazide drugs eg Bendrofluazide + Chlorothiazide
- blocks Na+/ Cl- at DCT
- preventing reabsorption of Na+ and Cl- .
- more Na+ in DCT
- more water move into tubule
- some Na+ move into blood again via other transporters
- transporters working harder
- ↑K+/H+ excretion at DCT
- hypokalemia + metabolic alkalosis
- removing excess Na+ stimulate macula densa
- increased RAAS
- more aldosterone
- Na+ reabsorption
- ↑K+/H+ excretion
- -hypokalemia + metabolic alkalosis
Thiazide drugs eg Bendrofluazide + Chlorothiazide
4*
- blocks Na+/ Cl- at DCT
- preventing reabsorption of Na+ and Cl- .
- more Na+ in DCT
- more water move into tubule
- some Na+ move into blood again via other transporters
- transporters working harder
- ↑K+/H+ excretion at DCT
- hypokalemia + metabolic alkalosis
- removing excess Na+ stimulate macula densa
- increased RAAS
- more aldosterone
- Na+ reabsorption
- ↑K+/H+ excretion
- risk of hypokalemia + metabolic alkalosis
Uses of thiazide drugs eg Bendrofluazide + Chlorothiazide?
- Hypertension - diuresis causes decreased BV + CO so causing vasodilatation to decrease TPR
- Heart failure - low ECF volume, CVP, CO
- Oedema
Osmotic agents eg Mannitol
- filtered but not reabsorbed
- high conc increases tubule osmolarity
- decrease reabsorption of H2O
- acts at PCT, DCT, collecting duct
- no effect on electrolyte excretion
Uses of osmotic agents eg Mannitol?
- Reduce intracranial + intraocular pressure : mannitol doesn’t enter CNS -> creates osmotic gradient –>H2O leaves CNS into plasma
- Prevent acute renal failure
- Prevent ANURIA - distal nephron can dry up when filtration is low
- Excretion of poisoning
Site 1, 2 of PCT
- 1
- reabsorption of Na+ with passive movement of Cl- + H2O
- net reabsorption of NaCl + H2O
- 2
- exchanging of Na+ and H+
- carbonic anhydrase makes H+ inside cell by making carbonic acid
- breaks into H+ and HCO3-
- H+ out of cell in exchange for Na+
- HCO3- reabsorbed with Na+
- H+ + HCO3- in lumen –> carbonic acid
- dissociate into H2O + CO2
- CO2 diffuses into cell so HCO3- reabsorbed
Site 3 of LoH
- transport of NaCl by Na+/K+/2Cl-
- thick ascending limb impermeable to H2O
- so interstitial region here (in medulla) is hypertonic
- reabsorption of H2O from collecting duct as it passes via medulla
Site 4,5,6 of DCT
- 4
- reabsorption of Na+ and Cl- followed by H2O
- 5
- aldosterone increases ENaC channels on luminal membrane and Na+/K+ on basolateral membrane
- Na+ reabsorbed via ENaC
- in exchange for K+ efflux into luminal membrane
- 6
- Na/H exchanger stimulated by aldosterone
5 + 6 can produce K+ loss (in response to Na
reabsorption) + alkalosis (due to increased proton
excretion) –> hypokalaemia + alkalosis
Carbonic anhydrase inhibitors eg Acetazolamide
2*
- mild diuretics
- inhibit carbonic anhydrase
- decrease formation of H+ in luminal cells of PCT
- loss of NaHCO3 into lumen
- loss of H2O
- Used in non-renal effects eg glaucoma as aqueous humor formation dependent on CA activity
K + sparing diuretics eg Spironolactone
- 5 + 6
- competitive antagonist of aldosterone
- inhibit ENaC channels
- less Na+ entering cells, reabsorption, inhibit Na+/K+ATPase
- less Na+ in, less K+ out, losing water
- Useful in CVS diseases linked to overproduction of aldosterone so volume overload
Aldosterone
-Steroid hormone synthesised by zona glomerulosa of
adrenal gland
-Released by Ang II on AT1 receptors
-Goes to DCT + collecting ducts
-diffuses via membrane + acts on nuclear receptors
(ligand-activated transcription factors)
-binds to mineralocorticoid receptor
-changes in transcription
-increase in luminal ENaC channel (sodium
channel) + Na+/K+ pump on basolateral membrane
-more Na+ into tubular cells
-increase [Na+] in cell so we increase Na+/K +pumps
-3Na+ out and 2K+ in
-Na+ from tubule lumen into plasma
-water follows
-conserving Na+, water –> increases blood volume + BP
-increased activity of Na+/K+ pump means more K+ taken from blood put into cell and passively secreted into lumen down conc gradient
-K+ excretion
-hyperaldosteronism –> hypokalemia
What does adrenal gland produce?
- Ouside adrenal gland is capsule
- Zona glomerulosa producing mineralocorticoid aldosterone
- Zona fasiculata producing glucocorticoids (primary
cortisol) - Zona reticularis producing sex steroids (weak androgens)
- Medulla producing catecholamines : A + NA
Liddle’s syndrome
- Rare genetic form of high BP associated with epithelial ENaC
- changes AA seq of ENaC
- open more often so increased renal Na+ reabsorption
- greater Na+ into cell –> blood
- greater movement of water into plasma
- increased blood volume + pressure sensed by RAAS system
- turn off renin release, Ang II, aldosterone release
- low renin + aldosterone
- continued increase in blood volume + pressure
- hypertension
Conn’s syndrome
Hypernatremia, hypokalaemia, alkalosis
-Primary hyperaldosteronism by overproduction of
aldosterone from adenoma of zona glomerulosa of adrenal cortex
-unregulated by renin so aldosterone releasing consistently
-increased ENaC so Na+ reabsorption
-increased Na+/K+ATPase driving Na+ into plasma
-water follows
-increase in ECF volume + BP
-JGCs detect BP so decrease renin secretion
-but irrelevant as tumour releasing aldosterone regardless of renin/Ang II
-K+ excretion by Na+/K+ pump due to aldosterone:
*ENaC driving Na+ into cell changes electrical gradient across cell, so K+ move into lumen
*increased permeability of apical membrane to K+
-aldosterone stimulates H+/K+antiport in intercalated cells
-removes H+ into lumen + brings K+ into cell
-however K+ reabsorption less than
-alkalosis + hypokalaemia
Renal artery stenosis
- narrowing of renal artery
- increased pressure drop across narrowing
- BP decreased in kidney
- decreased flow
- sensed by kidney
- secretes renin
- produces Ang II.
- vasoconstriction of vessels + increase aldosterone
- increased Na+ retention + water retention
- high BP
Factors that stimulate renin release?
- ↓ BP + BV –> ↓ renal blood flow via afferent arteriole mechanoreceptors
- ↓ Na at macula densa
- Symp nerve activation of β1 adrenoreceptors
Due to changes in baroreceptors activity + cardiac volume receptors
Atrial natriuretic peptide (ANP) + brain natriuretic peptide (BNP)
found in specialised cardiac myocytes
released by ↑ cardiac filling pressures (↑ECFV)
vasa recta
- Delivers O2 + nutrients to cells of LoH
- Permeable to both H2O + salts
- Could disrupt salt gradient established by LoH so acts as counter-current multiplier system as well
- vasa recta descends into renal medulla
- water diffuses out into surrounding fluids
- salts diffuse in
- vasa recta ascends - reverse occurs
- conc of salts in vasa recta same
- salt gradient at LoH constant
- water removed to not dilute longitudinal osmotic gradient
- medullary blood flow in vasa recta is slow
- sufficient to supply metabolic needs of tissue, but minimize solute loss from medullary interstitium
*Low BF in VR ~5% of renal BF to minimise solute loss from interstitium + maintains medullary interstitial gradient
-reabsorbed Na+ in descending carried to inner medulla equilibrating with interstitial fluid - ↑osmolarity
-Na+ in ascending returns to systemic circulation
-solute in ascending is product of flow rate + conc
If blood flow in VR increases then solutes washed out of medulla+ its interstitial osmolality decreased
If BF decreased - opposite
Amiloride
Blocks ENaC at *5
Reduces Na+ reabsorption and K+ loss
Captopril
- ACE inhibitor
- inhibits production of Ang II
- decrease aldosterone levels
Sources of acid?
-Metabolism of carbs + fats produces volatile CO2
CO2 + H2O ⇌ H2CO3 ⇌H+ + HCO3-
-Metabolism of proteins produces non-volatile acids
H2SO4 (from S-containing AA) + HCl
pH control
-ICF + ECF buffering systems
-Respiratory system - controls pCO2
-Kidneys - bicarbonate retention or secretion
via
Bicarbonate system
H+ + HCO3- ⇌ H2CO3 ⇌ CO2 + H2O
Phosphate system
H+ + HPO42- ⇌ H2PO4-
Protein system
H+ + Pr- ⇌ HPr
eg H+ + Hb- ⇌ HHb
Resp mechanisms of pH control
-chemosensitive area in medulla monitors [H+] based on CO2 that can cross BBB (CSF only buffered by HCO3-)
-plasma pH detected by peripheral chemoreceptors in aortic arch + carotid bodies
-signal to increase/decrease respiratory ventilation
-↓/↑ pCO2
-adjusted pH
H+ + HCO3- ⇌ H2CO3 ⇌ CO2 + H2O
Renal mechanisms of pH control
- formation + “reabsorption” of HCO3-
- secretion of H+
- bicarbonate, phosphate, ammonium buffer systems
- in all systems HCO3- being reabsorbed into blood
PCT controls pH
85% HCO3- reabsorbed + secrete H +
(no ATPase)
-HCO3- filtered by glomerulus
-[HCO3-]tubular fluid = plasma
-HCO3- + secreted H+ –> carbonic acid in tubular lumen
-carbonic acid dissociates -> CO2 + H2O
-catalysed by carbonic anhydrase on luminal brush border
-CO2 crosses tubular cell down conc grad
-CO2 recombines + H2O -> carbonic acid via carbonic anhydrase
-carbonic acid dissociates -> H+ and HCO3-
-HCO3- back into blood with Na+ via basolateral Na/HCO3 symporter
-H+ back into tubular fluid in exchange for Na+
-H+ appear in urine as water so urine pH unchanged
-net result = reabsorption of HCO3-, slight fall in tubular pH, no change in PCO2 of tubular fluid
Late DCT + collecting duct control pH
- in intercalated cells of late DCT + collecting duct
- H+ATPase pump vital
- H+ pumped in
- pH drops by end of collecting duct
- low [HCO3-] as most reabsorbed
- so H+ react with other buffers
Phosphate buffer
- phosphate ions poor buffers in ECF due to low conc but when filtered at glomerulus, phosphate exceeds Tm
- excess phosphate gets conc
- further secretion of H+ into lumen buffered by HPO42-
- effective buffer due to pK = 6.8 (close to pH of filtrate) + lipid-insoluble from –ve charge even after accepting H+ so can’t carry it back into blood
- H+ATPase pumps H+
- binds to mono-hydrogen phosphate + accepts it readily
- phosphate retains a –ve charge so traps H+ in urine
- HCO3- enters back into blood via antiporter with Cl-
Ammonium buffer
- tubular epithelium produces NH3 from glutamine with glutaminase
- glutamine broken down -> 2NH3 + α-ketogluterate
- α-ketogluterate broken down in TCA cycle -> 2 carbonic acid molecules
- dissociate -> 2H + and 2HCO3-
- H+ and NH3 -> NH4+
- sent into urine via antiport with Na+
- HCO3- back into blood with Na+
- NH4+ excreted into lumen acts as buffer for excess H+
- replenish ECF + ICF pools
- NH4+ secreted as ammonium salts
Role of phosphate + ammonium buffer?
prevent acidic urine
ammonia produces new bicarb to replenish
Respiratory acidosis
Alveolar hypoventilation
- eg obstructed airways
- CO2 accumulates
- ↑pCO2
- ↓pH
Respiratory alkalosis
Hyperventilation
- (eg anxiety)
- fall in CO2
- ↓pCO2
- ↑pH
Metabolic acidosis
Excessive production of acid by organs or exogenous acids
- (eg diabetic ketoacidosis)
- erxcessive loss of HCO3- from GIT from diarrhoea
- failure of acid excretion by kidneys
Metabolic alkalosis
Excessive ingestion of alkaline antacids
Excessive loss of H+ from GIT from vomiting
Excessive diuretic (thiazide) use
Chronic loss of Na+, K+, Cl- –> H+ secretion
Diabetic ketoacidosis
- Type I (enough insulin production in type 2 to avoid DKA)
- Excessive ketone production.
- Osmotic diuresis; glucose in urine –> water following by osmosis so dehydration + loss of electrolytes –> renal failure
- Form of metabolic acidosis
- body can’t glucose due to lack of insulin
- starvation state
- fat breakdown for energy
- producing ketones
- fruity breath
- ‘Breathing deeply’= Kussmaul breathing (deep freq breaths)
- reflex to stimulate CO2 loss from lungs to balance metabolic disturbance
- initial breathing response to metabolic acidosis is fast + shallow
- overtime deep, laboured, gasping = kussmaul breathing
Potassium balance
- Determines ICF osmolality, cell volume, ECF volume
- Affects vascular resistance by affecting polarisation of vascular SM cell)
- For heart + skeletal muscle cells
- Affects vascular resistance
Hyperkalaemia
- more K+ outside cell
- diff between K+ in cell vs outside cell
- RMP less negative
- more depolarised
Hypokalaemia
- less K+ outside
- huge diff
- outside less positive
- RMP more negative
- hyperpolarised
Factors that move K+ in/out cell
IN:insulin, aldosterone, β-adrengic stimulation, alkalosis
OUT:DM, Addison’s (aldosterone def), β-adrengic blockade, acidosis, cell lysis, exercise, increased ECF osmolarity
Causes of hyperkalaemia
- Acute (after prolonged exercise)
- Long term use of K+ sparing diuretics
- Addison’s disease
- Increased release from damaged body cells during chemo
Effect of hyperkalaemia
Plasma [K+]>7mM –> asystolic cardiac arrest
Treatment of hyperkalaemia
Insulin/Glucose infusion to drive K+ back into cells
Causes of hypokalaemia
-Long-standing use of K-wasting diuretics
(thiazide + loop diuretics)
-Hyperaldosteronism / Conn’s Syndrome
-Prolonged vomiting (indirectly via Na+ loss)
-Profuse Diarrhoea
Effect of hypokalaemia
↓ release of A, insulin, aldosterone
Treatment of hypokalaemia
Oral/IV K+
PCT ion reabsorption
- 60-70% of Na+ and K+ reabsorbed
- Constant fraction, amount reabsorbed changes with GFR
- Passive + paracellular transport via tight junctions
- K+ channels
LoH ion reabsorption
- 90% of filtered K+ reabsorbed in PCT + LoH
- Ascending impermeable to water
- Thick ascending limb contains Na/K/2Cl cotransporter that works by secondary active transport
- Water leaves in descending limb + ions leave in ascending limb
DCT + collecting duct ion excretion
- Excretion of K+ via principal cells of late DCT + CD
- Na+/K+ ATPase on basolateral membrane
- K+ high in cell so diffuses into blood
- K+ channel at luminal membrane
- ENac - aldosterone sensistive
- increased Enac
- Na+ flows in so K+ out into lumen
- more Na+ reabsorbed by principle cell
- more K+ secreted
- also K/Cl symporter on luminal membrane moving K+ out
3 determinants of K secretion control:
1) activity of Na-K-ATPase pump
2) electrochemical gradient
3) permeability of luminal membrane channel
What determines K+ secretion?
K+ intake
Blood pH
Tubular flow rate
How does aldosterone affect K+ secretion?
- Increased synthesis + activity of Na/K-ATPase at basolateral membrane = 3Na out, 2K+ in, build up inside then move out
- Upregulates epithelial ENaC at luminal membrane = Na+ in, K+ out
- Increased permeability of luminal membrane to K+
How alkalosis affects K+ secretion
- increase pH
- increase in Na+/K+ ATPase activity
- ↓plasma [K+]
- hypokalaemia
How acidosis affects K+ secretion
- low pH
- increased plasma [H+] inhibits Na+/K+ ATPase at basolateral membrane
- less K+ secreted
- hyperkalaemia
How tubular flow rate affects K+ secretion
- higher rates of distal tubular flow
- increases K+ secretion
- rapidly washed away
- low [K+] tubular fluid
- increases [K+] gradient :)
- ADH stimulates K+ conductance of luminal membrane
Addison’s disease
Hyponatremia, hyperkalaemia, acidosis, low cortisol + aldoesterone =Primary adrenal insufficiency -adrenal glands produce insufficient cortisol + aldosterone -body secreting more Na+ -low serum Na+ -body retaining K+ -hyperkalemia CAUSES : autoimmune, TB, CAH EFFECTS : Anorexia/weight loss, hyperpigmentation due to excess ACTH TREATMENT : Hydrocortisone - (replaces Cortisol) Fludrocortisone - (replaces Aldosterone)
Secondary adrenal insufficiency
- pit gland produces no adrenocorticotropin (ACTH) -common
- ACTH stimulates adrenal glands to produce cortisol
- Low ACTH output
- low cortisol production
- adrenal glands shrink due to lack of ACTH stimulation
Bladder
Transitional epithelium
Impermeable to salt and water
Permeable to lipophilic molecules
Sphincters
Internal – smooth muscle, involuntary control
External – striated muscle, voluntary control
Sensory innervation of bladder
- Pelvic nerve (S2-4) – para
- small myelinated Aδ Fibres (stretch + volume receptors)
- unmyelinated C fibres (pain from overstretching)
- Hypogastric nerve (T11-L2) – symp
- nociceptive C fibres
- Pudendal nerve (S2-4) – somatic
- nociceptive C fibres
Motor innervation of bladder
- Pelvic nerve (S2-4) – para
- contract detruser via Ach (mus R) + ATP (purigenic R)
- relax internal sphincter via NO (cGMP) + Ach (nicotinic R)
- encourages micturition
- Hypogastric nerve (T11-L2) – symp
- relax detrusor indirectly via NA (α-R) + directly via NA (β-R)
- contract internal sphincter via NA (α-R)
- inhibits micturition
- Pudendal nerve (S2-4) – somatic
- no effect on detrusor
- contract external sphincter via tonic release of Ach (on nicotinic R)
- inhibits micturition
Receptive relaxation
- Bladder empty
- sphincters closed
- tonic activity of symp + somatic nerves
- low bladder pressure
- Arrival of urine
- detrusor relaxes progressively
- symp activity inhibits paras transmission
- little increase in pressure
- sphincters still closed
Micturition reflex
- bladder starts to fill
- Aδ fibres sense stretching
- bladder is full
- internal sphincter relaxes
- urine flows into urethra
- flow of urine into urethra activates pudendal afferents
- tonic contraction of external sphincter removed by inhibition of somatic input
Modified by voluntary control
Incontinence
Stress = pelvic floor injury
Urge = detrusor instability
Neuropathic = head, spinal, peripheral nerve injury
Anatomical = vesicovaginal fistula
Atonic- overflow
Automatic- destruction of spinal cord: unannounced emptying
Neurogenic- freq + uncontrolled (inhibiting signals get interupted)
Treatments of incontinence
- Antimuscurinics to relax detrusor so less spasms of detrusor
- Bladder retaining (Kegel’s exercises ) to strengthen pelvic floor
- Botox toxin for spastic urethra
- Sacral nerve stimulation to re-establish micturition reflex
- Stem cells / 3D printed bladder
Effect of ions on cardiac contractility
Alkalosis: Increases contractility
Acidosis: Decreases since H+ competes with Ca2+ for binding sites on troponin
Effect of ions on calcium binding
H+ competes with Ca2+ ions for protein binding
- Acidosis: hypercalcaemia
- Alkalosis: less H+, more Ca2+ bound to proteins so hypocalcaemia
- muscle contraction dependent on intracellular Ca2+ not extracellular.
- hypocalcaemia refers to decreased extracellular Ca2+
- Ca2+ affects Na+ channel function at neuronal membranes
- plug it during Na+ influx
- modulating its permeability + excitability.
- in hypocalcaemia insufficient Ca+ blocks channel
- more Na+ influx
- destabilise membrane potential
- increased neuronal excitability leading to tingling, tetany
Role of kidney?
Control volume and composition of body fluids
Remove waste material from body (e.g. Urea)
Acid-Base Balance
Act as endocrine organ – EPO (controls RBC content), renin, produce active form of vit D 1α-hydroxylase
Constrictions of ureter
-Junction of ureter and renal pelvis
-Cross ext. iliac/pelvic brim
-Passage via wall of bladder
Retroperitoneal
Anatomy of kidney
- pyramids+medulla = parenchyma - functional portion of kidney
- within parenchyma 1 million microscopic nephrons
- filtered fluid from nephrons drain into papillary ducts
- drain into minor + major calyces
- filtrate becomes urine
- Nephron = functional unit, made up of glomerulus + tubule
- Types of nephrons : cortical + juxtamedullary
- Cortical nephrons lie in cortex (85% of nephrons), have short LoH which work during normal conditions
- Juxtamedullary nephrons have long LoH which work during periods of high activity
Ultrafiltration
- Forms glomerular fluid (passive ultrafiltrate of plasma where proteins + complete cells filtered out)
- Passive process driven by net pressure drop across glomerular membrane
1) Fenestrated capillary endothelium
2) Glomerular basement membrane = basal lamina (thick + fused), has holes with negative charges so anything dissolved in water (Na+) can pass through but RBCs can’t due to negative charges (unless barrier breaks down)
3) Podocytes surround capillaries of glomerulus that have 4nm filtration slits, enclose, strengthen vessels, allows them to withstand large filtration pressures
Filtration slits 4nm allowing small NaCl, glucose, urea not albumin so remain in blood
Nephrotic syndrome has appearance of protein in urine (proteinuria)
Starling’s principle
Fluid movement due to filtration across wall of capillary dependent on balance between hydrostatic + oncotic pressure gradient across capillary
REVISED
Jv = LpA { ( Pc - Pi ) - σ(πp - πg) }
Jᵥ: net filtration
Lₚ: Hydraulic conductance of endothelium, how Leaky endothelium is
σ: reflection coefficient for intercellular gaps
A: wall area
Hydrostatic pressures :
Pc : capillary BP
Pi : interstitial fluid pressure
Osmotic pressures :
πp = plasma proteins
πi = Interstitial proteins
πg = Glycocalyx proteins
(P꜀ - Pᵢ): hydraulic pressure diff
(πₚ - πᵢ): osmotic pressure diffHydrostatic pressure
pushing force by capillary pushing fluid into bowmann’s capsule
Oncotic pressure
pulling force by capsule also exerting pressure onto capillary
Starling force balance reversed
in peritubular capillaries BP falls below colloid pressure (due to protein being more conc in plasma) so greater force driving fluid back from tubule into capillary
- small amount of urine remaining in tubules
- along tubule, BP in afferent arteriole higher than colloid pressure when enter glomerulus
- net filtration pressure out of capillaries into tubule
- in efferent arteriole, pressure drops
- colloid pressure rises as fluid lost from capillaries
- so protein more conc –> exerting greater force driving fluid back from tubule into capillary
- so fluid being reabsorbed back into surrounding tissue + peritubular capillary where it comes into contact with tubule wall/nephron
- most reabsorbed otherwise volume depleted
- remaining in end is urine
GFR
=how much filtrate removed from blood each min NOT how much blood passes through glomerulus each min
Glomerular filtrate = same composition as plasma except protein free + no cellular components eg RBC
GFR ≈120ml/min
GFR ≈180L/day so plasma filtered 60 times daily
-Affected by hydrostatic, oncotic pressure, permeability of capillary filtration barrier, SA
-Indicator of renal function
-Fast filtration rate coupled with many nephrons so functions with only 1 kidney + reduced function in that kidney
GFR intrinsic control - autoregulation
Ensure renal plasma flow (RPF) + GFR constant with acute changes in BP
-Bayliss Myogenic Response: F = ∆P/R
Direct vasoconstriction of afferent arteriole with increase in perfusion pressure
-Tubularglomerular feedback TGF
Flow dependent signal detected in macula densa which alters tone (causes contraction) of afferent arteriole
Bayliss myogenic response
-Prevents BF during changes in BP
-Vital in renal, coronary, cerebral circulation
F = ∆P/R
F : BF, ∆P : change in pressure, R : resistance
When you increase perfusion pressure in kidney, you get short + brief increase in vessel radius so blood flow rises briefly but as smooth muscle stretches in afferent arteriole, it quickly constricts, reducing flow to normal :
- increase in perfusion pressure
- immediate increase in vessel radius (few seconds)
- blood flow rises briefly
- stretch on smooth muscle in afferent arteriole
- results in contraction
- reduction in diameter
- increase in resistance
- flow returns to control value in 30secs
Tubularglomerular feedback
GFR increases, so increased fluid flowing through tubule, fluid flows pass macula densa, change [NaCl] in luminal fluid, change osmolality so sensed by macula densa + juxtaglomerular cells, send signals to constrict afferent arteriole, change resistance of afferent arteriole. Outcome is to constrict afferent arteriole, so with increase flow, change in osmolality + [NaCl], elicits signal of ATP release from macula densa cells to activate JG cells –> increased resistance of afferent arteriole so decreased GFR :
- changes in flow alters luminal [NaCl]+luminal osmolality
- increase flow rate past macula densa
- macula densa detects change luminal osmolality
- renin released from juxtaglomerular cells of macula densa -vasoconstraction of afferent
- increased resistance in afferent
- decrease in hydrostatic pressure in glomerulus
- GFR decreases
GFR: extrinsic control – renal symp nerves
Renal symp nerves reduces GFR by resetting autoregulation to lower level
Occurs in:
Standing upright (orthostasis)
-Heavy exercise
-Haemorrhage and other forms of clinical shock
PURPOSE: Conserve body fluid volume
Symp aided by circulating vasoconstrictor hormones eg A, Ang, ADH
Excretion rate equation
= GFR – reabsorption rate + secretion rate
Measuring GFR
- Select substance that’s only filtered + not absorbed, secreted, metabolised
- Perfect standard is Inulin
- Rate of filtration through glomerular membrane = Rate of entry into bladder
- Inulin: inert polysaccharide freely filtered through glomerular membrane, not reabsorbed, secreted, metabolised but :
- prolonged infusion
- repeated plasma samples
- difficult routine clinical use
- Clinically use creatinine for GFR measurement but varies with muscle mass plus no infusion needed
Measuring eGFR
=estimated Glomerular Filtration Rate
Simple - requires one blood test but :
*sig error possible (especially for extremes)
*invalid for pregnant women (25% lower creatine), children, racial groups
-CKD Stages 1-5
-End stage CKD GFR <15 or on dialysis
Clearance
=plasma volume that’s completely cleared of substance by kidney per unit of time (ml/min)
-Inulin Clearance= 125ml/min = GFR
-Clinically creatinine is used
-Intrinsic inert substance, released at steady level from plasma, no infusion required, not reabsorbed but some secreted into tubule
-Creatinine clearance = 150ml/min
-However use of antibiotic Trimethoprim is competitive inhibitor of creatinine, competes with Crn for same transporters that secrete Crn from tubular blood into urine –> increase in serum levels of Crn
-Cs = (Us x V)/Ps
V: urine flow rate
Because inulin not reabsorbed, secreted, metabolised it varies with muscle mass
Renal plasma flow
= (amount of PAH in urine per unit time) / (diff in PAH conc in renal artery or vein)
Normal value is 660ml/min
Leaky podycyte
- loss of protein from blood
- less capillary oncotic pressure
- less fluid moving form ECF into blood
- nephrotic syndrome
Where does insulin act
Liver: glycogenesis, glycolysis, lipogenesis
Muscle: glucose uptake, AA uptake, glycogenesis
Adipose tissue: glucose uptake, FFA uptake, lipogenesis
Secretions of Islets of Langerhans?
insulin (β cells 65%)
glucagon (α cells 20%)
somatostatin (δ cells 10%)
Insulin precursors
Cleaving of C peptide = insulin from pro-insulin
Cleaving of signal seq = pro-insulin from pre-pro-insulin
- insulin polypeptide is originally pre-pro-insulin
- signal seq cleaved off –> proinsulin
- C peptide cleaved off –> insulin
- insulin receptor is tyrosine kinase
- becomes phosphorylated when activated
- activates further signaling pathways :
- inserting glucose transporters into membrane + glycogenesis
Phosphorylation of tyrosine kinase receptor
type of insulin receptor
ATP after large meal –> insulin
- β cell membrane has GLUT transporters
- glucose diffuses into cell
- glucose enters glycolysis + TCA cycle producing ATP
- ATP closes ATP sensitive K channels
- K+ can’t leave
- cell depolarises
- vgcc open
- Ca2+ enter
- exocytosis of insulin vesicles
Glucagon
Acts on liver to antagonise insulin
Stimulates: gluconeogenesis, glycogenolysis, ketogenesis
Glucagon synthesis
- peptide hormone starts as pro-glucagon
- cleaved to glucagon in α-cells
- pro-glucagon gene processed to give diff products GLP-1
- GLP-1 produced in lower intestine
- GLP-1 increases insulin secretion
- GLP-1 binds to receptors on β-cells
- leads to closure of K channels
- depolarises membrane
- aactivates vgcc
- exocytosis of insulin containing vesicles
- GIP not from proglucagon, but similar effects to GLP-1
- GIP released in upper small intestine
- GIP slows rate of gastric emptying
- potentiates insulin’s response to glucose especially after sugary/fatty meal
- both GLP-1 + GIP are incretins
- rapidly degraded by DPP-4
Prediabetes
Fasting blood glucose limit: 7 mmol/l
Random blood glucose limit: 11.1 mmol/l
Fasting levels high but not high enough for diabetes: impaired fasting glyceamia
Random levels high but not enough for diabetes: impaired glucose tolerance
Oral glucose tolerance test tests fasting levels then gives patients 75g of glucose + tests levels 2 hrs later
Diabetes
Type 1:
-β-cell destruction (due to autoimmune destruction) so no insulin production
-Develops in kids + young adults
-Genetic factors: HLA haplotypes DR3 + DR4
-Environmental factors: viruses, stress, drugs, toxins
-Treatment : ideal = pancreas/β-cell transplant
Type 2:
-β-cell dysfunction –> insulin deficiency
-Linked to insulin resistance
-Develops >40 yrs
-Common in: Indians, afro-caribbeans, high BMI
-Treatment: Insulin sensitisers+drugs to increase insulin production
HHS/HONK
- In Type II
- Develop symptoms of dehydration + high blood glucose levels
- Can be fatal
Micro vs macrovascular complications
MICRO
Retinopathy–damage to retina eventually –> blindness
Nephropathy–damage to nephrons –> renal failure
Neuropathy–damage to peripheral neurones so pins, needles, burning, tingling, loss of sensation –> amputations
MACRO = accelerated atherosclerosis as excess glucose breaks down endothelium
Heart attack–MAJOR RISK in diabetics
Stroke/TIA
Peripheral vascular disease–atherosclerosis in peripheral arteries causes reduced blood supply to feet
Mechanism of Thiazolidnedione
type of Glitazones – INSULIN SENSITISER
Bind to PPAR-gamma receptors to promote FA uptake
Mechanism of Gliclazide
type of Sulfonylurea
Blocks K+ATPase channels –> increase insulin production
Main side effect: HYPOGLYCAEMIA
Mechanism of Metformin
INSULIN SENSITISER Decrease hepatic glucose output Increase insulin R Increase GLUT4 expression Increase glycogen storage
ENS
-Digestive system’s own local neuronal complex.
-Lies entirely within in the gut
-Contains 100 million neurones
-Sub-branch of ANS, containing both symp +para nervous control
-Major functions:
Control of motility
Regulation of blood flow
Regulation of gastric + pancreatic secretions
Regulation of GI endocrine cells
Defence reactions
Myenteric plexus (Auerbach’s)
- Located between longitudinal + circular layer of muscles
- Control digestive tract motility
Submucosa plexus (Meissner’s)
- Located within submucosa of intestinal wall
- Senses changes within lumen
- Regulates GI blood flow
- Controls epithelial cell function
Symp vs para of GIT
-Symp nervous control (NA) Inhibition of GI secretions Inhibition of motor activity Contraction of sphincters Contraction of blood vessels -Para nervous control (ACh) Promotion of GI secretions Promotion of motor activity Relaxation of sphincters Relaxation of blood vessels
Cause of Gastro-Oesophageal Reflux Disease GORD
- Regurgitation of acidic contents via LOS into lower oesophagus
- Acid injures oesophagus –> inflammation
- Occurs when defect in anti-reflux barrier :
- LOS (closes after bolus passes)
- Abdo pressure acting on intra-abdo parts of oesophagus
- Pinchcock effect of diaphragm on oesophagus
- Oblique angle between oesophagus + stomach
- Plug-like action of mucosal folds (occludes lumen of gastro-oesophageal junction)
Swallowing
- Buccal:
- moistening food with saliva
- breaking down food via mastication
- formation of bolus
- pushed backwards towards oropharynx - Pharyngeal
- moves bolus from oropharynx -> oesophagus
- controlled by vagus via Ach on Nic receptors
- UOS relaxes - Oesophageal
- from oesophagus to stomach by peristalsis - initiated by swallowing + passes right throughout
- secondary peristalsis- initiated by local distension from distension point stomach
- LOS relaxes
Risk factors of GORD
- Obesity : extra pressure on stomach + diaphragm –> reflux
- Peptic ulcers –food doesn’t move from stomach to small intestine efficiently –> reflux
- Hiatal hernia : (akadiaphragmatic hernia) weaks LOS –> reflux
- Pregnancy : progesterone loosens LOS, foetus exerts pressure on stomach –> reflux
- Diabetes : patients also have gastroparesis, stomach takes longer to empty so contents of stomach –> reflux (also occurs in people whose stomach nerves and/or muscles unfucntional)
- Asthma : continuous coughing + pressure in lungs, medications loosen LOS –> reflux
- Connective tissue disorders: thicker muscular tissues keep stomach muscles from relaxing + contracting properly –> reflux
- Zollinger-Ellison syndrome: high levels of stomach acid from pancreatic or small intestine tumour (gastrinoma) –> reflux
- Smoking, alcohol, coffee
Complications of GORD?
- Acid regurgitation - water brash
- Oesophagitis
- Barrett’s Oesophagus
- Adenocarcinoma
- Oesophageal stricture (fibrosis) : lining of oesophagus continuously damaged by acid refluxing into it, scar tissue forms, builds up –> narrowed oesophagus so swallowing difficult + painful
- Bleeding (peptic ulcer may bleed)
Treatment of GORD
- Lifestyle : reduce risk factors, modulate exacerbation
- Pharmacological :
- antacids eg CaCO3 (Pepto Bismol) Mg(OH)2
- H2 receptor antagonists (Ranitidine [Zantac]+ Famotidine [Pepcid]
- PPI (Omeprazole [Prilosec])
- Metoclopramide (anti-emetic)
- Surgical : fundoplication
Mechanism of Ranitidine
- after meal
- gastrin produced by gastric parietal cells
- stimulates release of histamine
- binds to H2 receptors
- secretion of gastric acid
- Reduces secretion of gastric acid by reversible binding to H2 receptors
- inhibition of histamine binding to this receptor
- reduction of gastric acid secretion
- relief felt 60 mins + last 4-10 hrs so fast, effective symptomatic relief
- Decreased gastric acid secretion
- Reduced gastric volume
- Reduced [H+]
Achalasia
- Rare disease of muscle of the lower oesophageal body + LOS
- Impaired relaxation of sphincter, no contractions, peristalsis of oesophagus.
- Cause: unknown but degeneration of oesophageal muscles + nerves of myenteric plexus (motor supply of GIT) that control muscles
- Increased tone of LOS so can’t relax –> no peristalsis
- Affects mainly SM
- Abnormal function of LOS from impaired nonadrenergic, noncholinergic (NANC) inhibitory input
- Symptoms :
- Backflow (regurgitation) of food.
- Chest pain, which may increase after eating, or may be felt as pain in the back, neck, and arms.
- Cough
- Dysphagia
- Heartburn.
- Unintentional weight loss
- Complications : recurrent lung infections, oesophageal cancer,weight loss
- Diagnosis :
- via barium fluoroscopy
- manometry
Management of achalasia
- Endoscopic balloon/ Pneumatic dilation of LOS (+PPI)
- Heller’s cardio myotomy
- Fundoplication
- Peroral endoscopic myotomy
- Botox (botulinum toxin type A) as muscle relaxant
- Calcium channel blockers/nitrates
Mechanism of metoclopramide
-blocks D2 receptors (also excites 5-HT4)
-increased gastric motility + emptying
-increases ACh release
-increases LOS + gastric tone
-increased intragastric pressure
-improved coordination + emptying
Prevents nausea + vomiting triggered by most stimuli
Increases LOS tone
Increases peristalsis of duodenum + jejunum, tone + amplitude of gastric contractions
-Relaxes pyloric sphincter + duodenal bulb
-Gastroprokinetic effects so useful in treatment of gastric stasis
Indications: GORD, nausea due to surgery or cancer (chemo)
Role of dopamine in GIT
- Promotes relaxation of LOS + stomach
- Inhibits gastroduodenal coordination
- Increases ACh release
Mechanism of antispasmodic agents eg propantheline, mebeverine
-Musreceptor antagonist
-inhibits PSNS activity
-bowel relaxes
-reduces bowel spasm
Indications: IBS, diverticular disease (which may cause abdo pain)
Functions of stomach
Reservoir Digestion Mixing and mechanical disruption of food Kill pathogens Exocrine secretions Endocrine secretions Paracrine secretions
Parietal/oxyntic cells
- Located in fundic, cardiac, pyloric
- Stimulated by :
- Histamine - H2 via cAMP
- Ach - from para via vagus+ ENS stimulating M3 via Gq
- Gastrin - CCK2 receptors –> histamine secretion by ECL cells
- H+ formed from dissociation of H2O
- Produces HCO3- and H+
- HCO3- exchanged for Cl- on basal side of cell
- K+ and Cl- diffuse into canaliculi
- H+ pumped out of cell into canaliculi in exchange for K+ via H+/K+ATPase pump
- cellular export of H+ means gastric lumen is highly-acidic environment for digestion by promoting denaturing of ingested proteins
- Also produce INSTRINSIC FACTOR for absorption of vit B12 (or else def –> megaloblastic anemia)
Clinical sig of acid?
Peptic ulcers
- Antacids enhance natural tolerance of gastric lining
- Antimus eg pirenzepine or H2 antihistamines reduce acid secretion
- Proton pump inhibitors PPI more potent at reducing gastric acid production since it’s final common pathway of all stimulation of acid production
Chief cells
- Produce pepsinogen, gastric lipase, chymosin
- Stimulated by vagus + acid
- Converted into pepsin by HCl
Enterochromaffin (ECL) cell
- Located in fundic
- Produces histamine
- Stimulated by gastrin + vagus
Enteroendocrine (APUD) cells
- Located in fundic, cardiac, pyloric
- Producesgastrin, histamine, endorphins, serotonin, cholecystokinin, somatostatin
G cells
- Produces gastrin
- Directly stimulate gastric acid production
- Also stimulates histamine release
- Innervated by vagus
D cells
- Produces somatostatin
- Inhibit gastric acid production
Phases of gastric secretion
- Cephalic :
- triggered by thought, sight, smell of food
- transmitted by vagus
- acts on G + parietal cells to increase secretions
- responsible for 20% of gastric secretion - Gastric :
- stomach distension
- stimulates secretion
- responsible for 60% of secretions - Intestinal :
- presence of fat, acid, protein in duodenum triggers release of secretin
- decreases gastric acid secretion
Peptic ulcers
- Develops in lining of stomach, lower oesophagus, small intestine due to :
- Chronic NSAID use - reduce conc of prostaglandins in stomach which protect mucosa so erosion + damage
- H. pylori - causes chronic inflammation (gastritis), 80% of people with H. pylori infection are asymptomatic
- Complication of GORD
- Develop from imbalance between factors promoting mucosal damage vs mechanisms promoting gastroduodenal defence
- Gastric acid, pepsin, H. pylori, non-steroidal anti-inflammatory drug use) vs (prostaglandins, mucus, bicarbonate, mucosal blood flow)
- Aims of treatment:
- Reduce acid secretion with H2 antagonist
- Neutralize acid with antacids
- Remove H. pylori
- H2 receptor antagonists eg ranitidine, cimetidine
- inhibits histamine-stimulated gastric acid secretion *reduces pepsin secretion
- reduces basal + food-stimulated acid secretion
- Antacids eg aluminum hydroxide, magnesium carbonate
- neutralise gastric acid
- increase gastric juice pH
- More effective in treating duodenal ulcers
- Alginates added (forms layer above gastric acid to prevent acid reaching oesophagus)
H. Pylori
-Uses flagella + adhesins to adhere to mucosa
-Produces urease - converts urea -> NH3 + CO2 to buffer HCl
-Detected by urease test
-Patients swallow radioactively labelled urea
10-30mins later, if radioactive CO2 detected then presence of urease
-Stool test for antibody/antigen
-Treatment triple therapy:
*2 Antibiotics eg amoxicillin, metronidazole
*PPI eg Omeprazole, lanzoprazole, rabeprazole :
inactive at neutral pH, irreversibly blocks H+/K+-ATPase pump to reduce basal + food-stimulated gastric acid secretion
*Bismuth chelate can added
Diarrhoea
- Abnormal passage of loose, liquid stools > 3x, 200g/ daily
- Causes: infectious agents, toxins, anxiety, drugs, ulcerative colitis, crohn’s disease
- Main mechanism:
- increased motility of bowels + secretion
- decreased absorption
- loss of fluid, electrolytes, nutrients, HCO3-
- hypovolaemia (dehydration) + metabolic acidosis
- Dysentery: painful bloody, mucusy diarrhoea
- Aims of treatment :
- Maintain body fluids + electrolytes
- Antibiotics eg erythromycin for Campylobacter jejuni
- Modify secretion/ absorption balance
- Treatment :
- Anti-motility drugs (↓movement + secretion) eg loperamide
- Anti-spasmodics (↓movement) eg propantheline, mebeverine
- Antibacterials (often not needed)
Mechanism of Loperamide
Opioid receptor agonosist
- binds to peripheral 𝜇-opioid receptors
- spasmolytic agent reduces SM activity in GIT so reduces passage of faeces
- inhibit bowel function
- selective on GIT
- decreases passage of faeces + duration of illness
- For diarrhoea
Codeine + loperamide
- Anti-secretory action
- ↓ intestinal motility for diarrhoea
Bismuth subsalicylate
- ↓ fluid secretion in bowel for diarrhoea
- Safe for young children
- May cause tinnitus + blackening of stool
Constipation
-Bowel movements infrequent or hard to pass
-Causes:
*Reduced motility of large intestine eg elderly, (degeneration of GIT), damaged ENS
*Insufficient fibre
*Insufficient fluids
*Drugs eg codeine
*Hypothyroidism, hyperCa2+
*Pregnancy
-Management :
*Eat fibre + drink fluids
*Find underlying cause eg drugs, medical condition
-Drugs :
Bulk-forming laxatives
Stimulant laxatives
Osmotic laxatives
Faecal softener laxatives
Mechanism of bulk-forming laxatives eg methylcellulose, bran
- act like fibre by absorbing water
- softens stool + increases bulk
- bowel distension
- peristalsis
Mechanism of stimulant laxative eg senna, bisacodyl
- STIMULATE large intestine nerves
- incease water + electrolyte secretion from colon
- increased volume of stools
- bowel distension
- peristalsis
Mechanism of osmotic laxative eg lactulose
- contains substances that not absorbed/digested
- so remain in gut lumen
- substances hold water in stool by osmosis
- maintains its volume
- distension of colon
- peristalsis
Mechanism of faecal softeners eg docusate sodium(also stimulant laxative)
- wetting + softening of stools by addition of water + fat
- improved peristalsis
Control of vomiting
-Forcible ejection of stomach contents from mouth
-Controlled by 2 main brain centres in medulla oblongata vomiting centre + CTZ (chemoreceptor trigger zone)
VC :
-Initiates + controls retrograde GI contractions –> vomiting
-Responds to stimuli from various parts of body under stress/diseased
CTZ :
-stimulated by drugs + toxins
-stimulates VC to initiate emesis to remove toxin from body
-Also SNS activation: sweating, increased HR, pallor
Causes of vomiting
GI infection Distesion stomach or small intestine Motion sickness Drugs eg opioids Increased pressure in skull eg tumour Intense pain Sight, smell, emotional circumstances Pregnancy
Vomiting
Loss of oodf, electrolytes (Na+, K+, Cl-, HCO3-), gastric acid (HCl), bile, blood
Results in :
-Hypovolaemia (dehydration)
-Metabolic alkalosis (due to loss of HCl)
-Malnutrition –> death
CVS adaptation, renal adaptation, behavioural (eg being thirsty so drinking more)
Bismuth chelate
- forms base over ulcer crater
- adsorbs pepsin
- causes HCO3- and prostaglandin secretion
- protects gastric mucosa
- Also toxic against H. pylori
- But black tongue + stool
How can NSAIDs contribute to ulcer formation?
=Non-steroidal anti-inflammatory drugs (eg ibuprofen)
Inhibit prostaglandin synthesis
-Prostaglandins protect stomach mucosa by :
*stimulating bicarbonate + mucus secretion
*inhibiting H+ secretion
*promoting vasodilation (blood flow to mucosa)
So drugs (eg celecoxib, rofecoxib) preferred as it blocks only COX-2
Hemolytic Uremic Syndrome (HUS)
caused when EHEC E. coli strain enters blood + causes acute kidney failure (so high urea in blood – uraemia), haemolytic anaemia (destruction of RBCs so anaemia), thrombocytopaenia
Patterns of blood flow?
Laminar : most vessels
Turbulent : ventricles, aorta, atheroma
Bolus : capillaries
Darcy’s law
-About flow of fluid (blood)
-Flow = ∆Pressure / ∑Resistance
so BF = BP / TPR
BF = CO
so BP = CO x TPR
Q = P1–P2 / R
Q : Flow
P1-P2 : Pressure diff
R : Resistance to flow
Flow = Pa–CVP / TPR
Bernoulli’s Law
Flow = Pressure (PV) + Kinetic (ρV2/2) + Potential (ρgh)
ρ : fluid mass
Arterial Blood Pressure
- Pressure exerted by blood on vessel walls (generated by left ventricular contraction)
- Involves interactions between: systolic, diastolic, pulse, mean blood pressure
TPR
Controls blood flow + pressure
Arterioles involved
Controlled by : Poiseuille’s law, Bayliss myogenic response
Poiseuille’s Law
Resistance = 8ηL / πr^4
η : viscosity
Veins
Thin-walled, collapsible, voluminous Contain SM with symp innervation Contain 2/3rd of blood volume Act as reservoir Useful in exercise + haemorrhage (*Starling’s law)
Vasoconstrictor Nerves
Act directly on VSMCs
ONLY symp
NA acts on α1-receptors
Produces vascular tone (1 AP per sec)
Vasoconstrictor hormones + where they act
-Act directly on VSMCs : Adrenaline (α1-receptors) Ang II (AT1 receptors) ADH (V1 receptors) Endothelin-1 (ETA1 receptors) TXA2 (TP receptors)
Mechanism of vasoconstrictor hormones
- Stretch activates these receptors – myogenic response
- receptors are Gq
- linked to PLC
- hydrolysis of PIP2 -> DAG + IP3
- IP3 acts on SR to cause release of Ca2+
- DAG increases excitability, gets more depolarised, activates vgcc, release of Ca2+
- influx of Ca2+ from external fluid
- Ca2+ activates Calmodulin
- drives myosin light-chain kinase
- phosphorylation of myosin heads
- interaction between myosin-actin
- contraction
Vasodilator nerves
Act INDIRECTLY via endothelium
Symp + para
ACh/VIP act on endothelium, endothelium produces NO + PGI2 –> smooth muscle relaxation
Vasodilator Hormones
-Act INDIRECTLY via endothelium :
Histamine (H2 receptors)
Bradykinin (B receptors)
Adrenaline (β2-receptors)
How does NO cause vasodilation?
- shear stress in endothelium (or IF) stimulates Nitric Oxide Synthase (eNOS)
- produces NO
- NO diffuses from endothelium cell into VSMC
- stimulates G pathway
- stimulates Guanulate Cyclase (GC)
- produces cGMP from GMP
- cGMP activates PKG
- PKG causes vasodilation
How does Prostacyclin (PGI2) cause vasodilation?
- shear stress (or IF/Ach) on endothelium
- membrane lipids into PGI2 via cyclooxygenase (COX)
- PGI2 acts at Prostanoid receptor (PGI2) on VSMC’s
- drives A pathway
- Gs -> AC -> cAMP -> PKA
- PKA causes vasodilation
Catecholamines (A + NA)
More β2 in skeletal muscle + coronary vessels
A :
-higher affinity for β receptors
-vasodilation on skeletal + cardiac muscle
-vasoconstriction on other tissues
-give for actions on α1 (vessels) + β1 (heart) eg anaphylaxis
NA :
-higher affinity for α receptors
-vasoconstriction on skeletal, cardiac, others
-give for actions on α1 (vessels) eg heart failure - cardiac-protective
Reflex Receptors
PRESSOR : switch ON reflexes (↑ CO, TPR, BP)
-Arterial chemoreceptors (aortic body, carotid body)
-Muscle metaboreceptors
-Nociceptive sympathetic afferents
DEPRESSOR : switch OFF reflexes (↓ CO, TPR, BP)
-Baroreceptors (aortic arch, carotid sinus)
-Ventricular mechanoreceptors
Capillaries
Smallest diameter
Endothelium ONLY (1 cell thick)
Semi-permeable
Large SA (ideal for solute/fluid exchange)
Solute transport
Solutes are exchanged by passive diffusion
- Into cells : O2, glucose, AA, hormones, immune cells
- Out cells : CO2, urea
Fick’s law of diffusion
Js = - DAΔC / x
Js : mass per unit time
D : diffusion coefficient of solute – ease through solvent
A : area
ΔC / x : conc gradient (C1-C2) across distance x
negative value : flowing ‘down’ a conc gradient
Types of capillaries
- Continuous capillaries (least permeable) : in skin, CNS, muscle, lung
- Fenestrated capillaries : in exocrine glands, glomerulus, intestinal mucosa
- Discontinuous capillaries (most permeable) : in liver, spleen. bone marrow
Glycocalyx
barrier so plasma proteins move from lumen into interstitial space via vesicle system not via intercellular spaces
Lymphatic System
-Returns excess solutes/fluids back to CVS
-Lymph vessels have valves + SM
-Overall control of ECF balance depends on:
capillary filtration
capillary reabsorption
lymphatic drainage
Factors that promote filtration vs reabsorption
FILTRATION increased P꜀ increased πg increased Lₚ decreased πₚ REABSORPTION decreased P꜀ increased πₚ
Cell based model of coagulation
- damaged tissue releases TF
- TF activates 7a
- 7a initiates thrombin required for amplification
- 8a + 9a on platelet surface activates 10a
- 10a has cofactor 5a
- 10a + 5a induces prothrombin
- prothrombin -> thrombin
- thrombin induces fibrinogen -> fibrin
Fibrinolytic system
- endothelial cells release tPA
- tPA activates plasminogen
- plasminogen -> plasmin
- plasmin breaks up clot
- forming fibrin fragments + D-dimers
Preload - Starling’s law
Energy of contraction of cardiac muscle is proportional to muscle fibers length at rest
-greater venous return
-stretch of muscle fibers
-more cross bridge formation
-increased sensitivity to Ca2+
-greater contraction
-greater SV
-SV increases in response to increase in volume of blood filling heart (end diastolic volume)
-Starlings predominates at low ventricular volumes
-Laplace’s predominates at high ventricular volumes
-Excess filling –> overstretched muscle –> decreased SV
so consider when fluid replacement
Afterload – Laplaces Law
P = 2Sw / r or S = P x r / 2w
- So radius proportional to wall stress
- Opposes ejection of blood from heart + Starling’s at rest
- Determined by wall stress through heart wall
- Increases if pressure + radius increase
- Decreases if wall thickness (explains hypertrophy in heart failure)
- so Laplace good with small radius + bad with large
- increased preload
- increased chamber radius
- increases afterload
- In healthy heart - Starling’s law > Laplaces for maintained ejection
- Facilitates ejection during contraction –>decreased chamber radius –>reduces afterload in ‘emptying’ chamber –> ejection during reduced ventricular ejection phase 4
- In failing heart chambers dilated –> increased radius –>afterload–>reduced ejection
- Increased arterial BP –>wall stress –> afterload –>reduced ejection
Cardiac electrical cycle
- SAN contraction generating nerve impulses
- travel through heart wall
- P wave (atrial contraction)
- AVN (when impulses from SAN reach AVN – PR interval – short delay to allow full contraction of atria + emptying prior to ventricular contraction)
- bundle of His splits into 2 bundle branches (go to either ventricles)
- impulses carried down from centre of heart to ventricles
- bundle branches taper into purkinje fibres
- stimulate myocardial cells to contract
ECG
P wave = atrial depolarisation
PR segment = AVN delay
QRS = ventricular depolarisation
ST segment = time which ventricles contract + emptying
T wave = ventricular repolarisation
TP interval = time which ventricles relax + filling
SAN: Pacemaker potentials
Phase 4: Pacemaker potentials, If channels, hyperpolarisation activated Na channels
Phase 0: Depolarisation, Ca channels, influx via vgcc
Phase 3: Repolarisation, K Channels, efflux
Atria/Ventricular action potentials
Phase 0: Na influx Phase 1: Na channels close Phase 2: Ca influx, plateau maintains refraction so no AP firing (allows proper filling + ejection) Phase 3: K efflux Phase 4: Na-K pump active
Cardiac cycle
1) Diastole - ventricle filling, atrial contraction
- blood enters atria, moves into ventricles
- atria p > ventricles
- tri/bicuspid valves open
- filling aided by atria contraction
2) Systole - ventricular isovolumetric contraction
- ventricle p > atria
- tri/bicuspid valves close
- contraction on closed ventricle
- p ↑ in chamber
3) Diastole - eject, atrial filling
- ventricle p> aorta/pul artery
- aortic/pul valves open
- ejection
- blood also enter atria
4) Systole - ventricular isovolumetric relaxation
- aorta/pul artery p> ventricles
- aortic/pul valves close
- ventricle relaxes to receive blood
Heart sounds
S1 - Lubb – Mitral + tricuspid close
S2 - Dubb – Aortic + pulmonary close
S3 - Turbulent blood flow into ventricles
S4 - Forceful atrial contraction against a stiff ventricle
Lubb = Start of ventricular systole
Dubb= Start of ventricular diastole
Cardiac contraction
- AP upstroke Na+ depolarises T-tubules
- activates vgcc
- local Ca2+ influx
- Ca2+ binds to RyR on SR (close to T-tubules)
- CICR
- Ca2+ binds to troponin
- displacement of tropomyosin/troponin complex
- exposing active sites
- myosin bind to active sites on actin
- myosin head ATPase activity releases energy
- ATP to ADP
- slide filaments - contraction
How does Ca2+ influence contraction
Greater rise in [Ca2+]i -> more sites exposed -> more crossbridges -> more contractility - inotropic effect
- Shortening of the sarcomere.
- Z disc distanceshortens
- H zonedisappears
- Dark A bandincreases due to overlap
- Light I bandshortens.
- myosin head attaches to actin (high energy ADP + P configuration)
- power stroke: myosin head pivots pulling actin filament toward center
- cross bridge detaches when new ATP binds to myosin
- tilting of myosin head when ATP hydrolysed
- another cross bridge can form
- decrease [Ca2+]
- blocking of actin site by tropomyosin
Ca2+ removal
- K+ stimulated T-tubule repolarisation
- vgcc closes
- no Ca2+ influx or CICR
- decrease [Ca2+] via Na+/ Ca2+ exchanger (30%)
- Ca2+ SR uptake via Ca2+ ATPase (SERCA)
- mitochondrial Ca2+ uptake
Cardiac glycosides
- Inotrope = Agents that alters force of contraction eg Digoxin
- blocks Na/K-ATPase
- more Ca2+ taken into SR
- more Ca2+ released upon next depolarisation
- Decrease rate of contractions by acting on Na/K-ATPase pump
Digoxin
- potent inhibitor of Na/K/ATPase
- which pumps sodium out + potassium into cell
- [Na]i to increase
- decreases activity of Na/Ca exchanger
- less Ca2+ pumped out of cell thus
- more [Ca2+]i
- more Ca2+ to bind to TnC
- increases contractility – inotropy
Symp NS on contractility
-stimulation of β1-adrenoceptor
-increases PKA :
*PKA phosphorylates vgcc –>increases contractility
*PKA phosphorylates K+ channels + SERCA –>increased relaxation
Diastolic time maintained allowing time for ventricle filling + coronary perfusion
Diff between force of contraction vs contractility
- Force of contraction effected by preload (volume of venous return) + contractility
- Contractility depends on how much [Ca2+]i
Heart failure
=Clinical syndrome where heart unable to maintain sufficient blood flow to meet body’s needs
Structural/functional disorder impairs ability of ventricle to fill/eject blood
-increased ventricular filling
-increased contractility
-increased SV
-eventually plateau
-overstretching of ventricles
-decreased contractility
-reduced ability to cross link actin-myosin filaments
Causes of HF = ischaemic heart disease, myocarditis, toxic:alcohol, chemotherapy, muscular dystrophies, glycogen storage diseases
DIAGNOSIS
BNP (released when muscle is strained) cleaved to NTProBNP + BNP – means NtproBNP as it’s more stable
If elevated then ECG
-Commonest cause for emergency admissions in over 65’s
-Men > women
-Estimated to increase by 50% by 2030
Risk factors :
smoking, previous MI, hypertension, diabetes, abdominal obesity, psychosocial stress, high ApoB: ApoA ratio
(ApoB + Apo A are apolipoproteins involved in lipid transport, ratio indicates cholesterol, if low good)
Compensatory mechanism of heart failure
- Preload reduced by vasodilators (GTN) to reduce load of heart by dilating peripheral vasculature + diuretics
- Maintain SV (dilation) to increase SV (starling’s law) - only maintained temporarily until pressure in stretched ventricle increased –> restriction to filling + increased venous pressures
- Increase HR when SV falls to maintain CO temporarily (so new MI patient tachycardic) so decrease heart blood volume to decrease afterload because with dilated heart there’s afterload for a given arterial pressure (La Place’s law)
Coronary circulation
- Coronary arteries arise from ascending aorta
- Right side: right coronary artery, right marginal artery, posterior interventricular artery
- Left side: Left coronary artery, circumflex artery, anterior inter-ventricular artery (LAD)
- All drain into RA via coronary sinus
- Functional end arteries = no collateral supply
Right vs left heart failure
SYMPTOMS
-Right ventricular failure = back pressure in RA -> pressure in SVC + IVC -> increases JVP -> oedema, right and left pleural effusion, ascites (swelling in abdomen)
-Left Ventricular Failure = Back pressure into LA + pulmonary veins :
*pulmonary oedema (leak of fluid into alveoli)
*dyspnoea (shortness of breath)
*orthopnoea (worse when lie flat due to increased oncotic pressure when lying down)
*paroxysmal nocturnal dyspnoea (sudden shortness of breath at night
Both simultaneously = congestive heart failure
Classification of heart failure
-Reduced EF vs Preserved EF (Ejection fraction is proportion of blood that leaves heart every time it contracts)
-Acute vs Chronic
-Left vs Right Ventricular failure
-NYHA classification scale :
Class 1 = No limitations
Class 4 = Breathless at rest, unable to carry out any physical activity without discomfort
What happens during heart failure
Starling’s Law:
-Myocyte damage = reduced ability to contract
-Less blood pumped out into circulation so less coming back
-Lower preload = Starling’s law breaks down
Laplace’s Law :
-Reduced energy of contraction = afterload harder to overcome
-Effect of Laplace’s law increases as more pressure needed to push blood out of heart
-SV + CO decrease –> low cardiac perfusion –> ischaemia –> HF
Ventricular Dilatation
- muscle fibres stretch
- increases contractility - Starlings law
- increases ventricular volume
- increased EDV
- Increases ventricular volume –> increased EDV
- Increases contractility because when fibres unstretched, mechanical interference between overlapping fibres reduced, so potential for cross bridge formation increased –> Starling’s
Myocardial hypertrophy
Increasing wall thickness :
-Increases force of contraction since more sarcomeres present to contract –> increases CO
-Reduces wall stress (wall stress + wall thickness inversely proportional) –> increases CO
BUT
-Hypertrophy = increased metabolic demand so difficult to sustain its own supply –> heart failure
Neurohormonal compensations - RAAS
- low BP activates RAAS
- juxtaglomerular cells release renin into bloodstream
- converts angiotensinogen -> Ang I
- Ang I transported to lungs
- Ang I -> Ang II by ACE
- Ang II = reabsorption of Na+/H2O + contraction of vessels
- constriction of arterioles increases TPR + BP
- so blood faster around body
- increased reabsorption of Na+/H2O –> increase preload, EDV, SV, CO
BUT
- Vasoconstriction increases afterload,
- Increased CO = Increased preload
- Both increases cardiac work
Neurohormonal compensation - symp drive
- decreased CO detected by baroreceptors
- central + peripheral chemoreflex activation induce A, NA, VP release
- adrenergic activation increases HR + contractility via vasoconstriction
- increased afterload
- increased cardiac work
- myocyte damage
Treatment of heart failure
Treatment : TRIPLE THERAPY
-ACE inhibitor eg senalpril, losartan, elanapril
-β-blockers - negative inotrope cause less contractility so less adrenaline binding to β2 = less symp drive so decrease HR + BP
-Aldosterone antagonist eg losartan, decrease vascular resistance so decrease BP
Other options : heart transplant, left ventricular assist devices (external cardiac pumps), biventricular pacing
What happens to our coronary vessels when we run?
- During exercise, heart beast stronger, faster
- Increased cardiac demand
- Coronary vessels vasodilate to meet these demands
- More BF to heart tissue
Angina pectoris
- Crushing chest pain
- Narrowing/blockage of coronary artery = O2 demand exceeds supply
- Stable = Predictable, chest pain on exertion
- Unstable = Chest pain due to thrombus formation
- Variant (Prinzmetal) = Vasospasm of coronary arteries, causes chest pain at rest
Stable angina
- At rest coronary vessels maximally vasodilated
- Further exertion will lead to an increase in cardiac demand
- Demand > supply –> ischaemia
- Ischaemic products stimulate symp nociceptive afferents = chest pain
Risk factors + treatment
Risk factors for angina : High BP Tachycardia Increased force of contraction Cold weather Large meal Treatment for angina : Nitrates Beta blockers Calcium channel blockers Antiplatelet drugs
Myocardial Infarction
- Tissue death as a result of vascular occlusion
- ST elevation on ECG
- As opposed to angina has ST depression
Development of heart
- 4 chambered heart tube forms
- cardiac looping
- AV canal divides into right and left channels
- atrial septa forms
- conotruncal cushion forms leading to division of outflow tract
Patent Foramen Ovale
- In foetus, circulation doesn’t need to go through lungs
- gets O2 from placenta
- blood in foetal heart shunted straight from RA to LA
- hole in interatrial wall = foramen ovale allows for this
- Normally closes up after birth
- Patent foramen ovale = doesn’t close
Ventricular Septal Defect
- Most common congenital heart defect
- Hole in interventricular septum
- Left side of heart has higher pressure than right side
- Oxygenated blood from left side passes to right side, mixed with deoxygenated blood
Tetralogy of Fallot
Overriding aorta
Pulmonary stenosis
Ventricular septal defect
Right ventricular hypertrophy
+ VSD both common in Down’s syndrome
EQUATIONS
CO = HR x SV SV = EDV – ESV EF = SV / ESV BP = CO x TPR Velocity = blood flow / CSA Pulse pressure = systolic - diastolic Mean arterial pressure = diastolic x (1/3 pulse pressure) Stroke work = change in ventricular pressure x change in volume
Anatomy of pituitary gland
-Sits in sella turcica within sphenoid
Cell types = Chromophobes + Chromophils
-Chromophils :
Acidophils - GH + prolactin
Basophils - TSH, ACTH, LH, FSH
Development of pituitary gland
Embryologically :
- Anterior pituitary develops from Rathke’s pouch (part of oropharyngeal ectoderm)
- Posterior pituitary + pituitary stalk develop from part of neuroectoderm
- Finger of ectoderm grows upward from mouth roof =Rathke’s pouchand becomes ANTERIOR pituitary or adenohypophysis
- Finger of ectodermal tissue evaginates ventrally from diencephalon of developing brain - extension of ventral brain becomes POSTERIOR pituitary or neurohypophysis
Hormones of pituitary
Ayy Ohh, it’s the FAT GP
Posterior :
ADH - retains water
Oxytocin - uterine contraction + breast milk release
Anterior :
FSH + LH - reproductive control
ACTH - regulates adrenal cortex
TSH - controls production of thyroid hormones
GH - controls growth (releases IGF-1 cause bone + muscle growth)
PRL (prolactin) - breast milk production
eg of hypothalmic factor
TRH, CRH, LHRH
Prolactin
Has diff control to all pituitary hormones :
- Tonic release of DA inhibits prolactin release
- Positive feedback
Prolactinoma
Features of prolactin excess (hypogonadism):
Infertility, Amenorrhea, Impotence, reduced libido.
TREATMENT:
Dopamine agonists, Cabergoline, Bromocriptine
NOT surgery
Non-functioning pituitary tumours
-30% of all pituitary tumours
-No symptoms of hormone excess production
-Cause symptoms due to space occupation :
Headache
Visual field defects (bitemporal hemianopia)
Nerve palsies
Interfere with rest of pituitary function
-Treatment :
Surgery + Radiotherapy
No effective medical therapy
Pituitary Function with an Expanding Tumour
- Lose function based on biological importance
- Prolactin levels INCREASE due to compression of pituitary stalk
Treating pituitary adenomas
Surgery - Transphenoidal.
Radiotherapy - slow.
Drugs - Block hormone production and release.
Hypopituitarism
Treatment = replace what is lacking Thyroid -> thyroxine Sex steroids –> Testosterone, oestrogen Reduced cortisol -> Hydrocortisone Reduced GH -> Growth Hormone
Diabetes insipidus
Underproduction of ADH : -Cranial - lack of production -Nephrogenic - receptor resistance Diagnosis : -Polyuria (>3l) -Polydipsia -Plasma Na+ INCREASE -Plasma osmolality INCREASE -Urine osmolality DECREASE -Urine Na+ DECREASE Investigation : -Water Deprivation test – STOP if patient drops 3% their body weight -Normal = small amount of conc urine -DI = large amount of dilute urine -desmopressin (DDADH) test (mimics ADH) : *cranial DI = urine production stops *nephrogenic DI = still produce urine
SIADH
Excess ADH from : -Brain injury/infection -Lung Cancer/infection asthma IPPV -Metabolic : hypothyroidism, Addisons Low serum osmolality, low serum Na conc, high urine osmolality, high urine Na conc
Thyroid hormones
T4: major form released to blood, less active (prohormone)
T3: active form, converted in target cells
T4 -> T3 by deiodinases (removes one of iodine’s)
Thyroid hormone synthesis
- follicular cells make thyroglobulin in ER
- released into colloid by exocytosis via apical membrane
- iodide taken up from blood into follicular cell via Na/I symporter on basolateral membrane
- transported into colloid via pendrine cotransporter
- transports Cl- in and I- out
- TPO converts 2I-s -> I2
- TPO also iodinates thyroglobulin
- forms MIT or DIT groups - moniodotyrosine or diiodotyrosine
- TPO conjugates tyrosine residues
- form T4, T3, RT3 (biologically inactive)
- iodinated + conjugated thyroglobin moves back into cell by endocytosis
- lysosomes bind to vesicle + cleave peptide bonds
- so T3 + T4 separated off
- move into blood via MCT receptor on basolateral membrane
- most T3 + T4 bound to TBP, albumin – for transport + increases half-life
- T3 + T4 diffuse into tissues via MCT
- T4 (inactive) -> T3 (active) via deiodinases
Functions of TH
Increase metabolic rate :
-Number + size of mitochondria, enzymes in metabolic chain, Na/K-ATPase activity
-Positive inotropic, chronotropic effects on heart
-Synergizes with symp NS
Energy metabolism :
-Partially antagonizes insulin signalling
-Gluconeogenesis, lipolysis
Growth + development
Control of TH synthesis
- Controlled by the HPT axis
- TRH released into portal circulation -> ant pit gland -> stimulates thyrotrophs to secrete TSH
Actions of TSH
- Increases iodine uptake
- Stimulates TPO reaction involved in TH synthesis
- Stimulates uptake of colloid
- Induces growth of thyroid gland —> goitre
Hypothyroidism
-TH deficiency
-High TSH
-Low T3, T4
Primary Hypothyroidism (Hashimotos disease) :
-Autoimmune thyroid destruction
-Low TH, high TSH
-Lethargy, intolerance to cold
-Diffuse goitre
-Lack of growth + development
Secondary hypothyroidism so all low
-From deficient TSH secretion from cellar lesions eg pituitary tumor or craniopharyngioma
Causes:
-Hashimotos
-Post-thyroidectomy (due to previous hyperthyroidism)
-Post RAI (radioactive iodine)
-Iodine deficiency
Investigations:
-Test TSH + T3/4 levels
-Test for TPO activity
Treatment: Levothyroxine
Hyperthyroidism
Primary: thyroid gland problem
Secondary: pituitary regulation problem so all high
-Low TSH
-High T3, T4
Primary Hyperthyroidism (Graves disease) :
-Autoimmune
-High TH, low TSH
-Weight loss, tachycardia, fatigue
-Diffuse goitre (TSH receptor stimulation)
-Vitiligo
-Opthalmopathy : exopthalmos, periorbital oedema, lid retraction/lid lag, ophthalmoplegia
Antithyroid medications (Block TPO enzyme):
Carbimazole
Methimazole
Propylthiouracil
Thyroid Storm – Extreme thyrotoxicosis (due to stressful illness or thyroid illness)
Symptoms: delirium, severe tachy, vominting, diarrhoea, dehydration, high fever
Adrenal steroidogenesis
- cholesterol into zona glomerulosa
- cholesterol -> pregnenolone
- pregnenolone could :
- Stay in cell + converted to progesterone
- Enter back into blood + move down to zona fasiculata under action of new enzyme become a new molecule
Types of Steroids
-Mineralocorticoids – Aldosterone
-Glucocorticoids – Cortisol
Metabolism – prevent fatal hypoglycaemia
Immune function
-Androgens – Sex steroids
Testosterone
Role of cortisol
-Increases Plasma Glucose Levels INCREASE in Gluconeogenesis INCREASE in Glycogenesis INCREASE in Glycogen Storage DECREASE in Glucose Utilisation -Proteins are broken down so AA released -Increased Lipolysis -Na+ and H2O Retention (Maintains BP) -Anti-Inflammatory (inhibits AA production + COX activity) -Increased Gastric Acid Production
Cushing’s Syndrome
Excess GC/cortisol in the blood
Adenoma producing ACTH in pituitary gland
-Changes in protein + fat metabolism : Change in body shape Central obesity Moon Face Buffalo Hump Thin skin, easy bruising Osteoporosis Diabetes -Salt + Water Retention : High blood pressure Fluid retention -Changes in sex hormones : Excess Hair Growth Irregular periods Problems conceiving Impotence TREATMENT : -Localisation + removal of tumour – adrenal, pituitary or ectopic ACTH tumour (often SC lung tumour). If single adrenal tumour, then short term steroid replacement therapy required after surgery -Cortisol Production Blockers: If can't have surgery
ACTH receptor
- Part of melanocortin group of receptors
- ACTH can bind to other melanocortin receptors instead
- One of the other receptors controls skin pigmentation
- Excess circulating ACTH can affect skin pigmentation (eg in Addison’s)
Muscles of Inhalation
Quiet/resting Inhalation: -diaphragm forms floor of thoracic cavity -contracts + flattens -increase vertical diameter of thoracic cavity -contraction pulls + expands lungs Heavy/forceful Inhalation: -external intercostals contract -accessory muscles -SCM -3 scalenes
Movement of Ribs
PUMP HANDLE : Elevation of ribs to increase in antero-posterior diameter of thoracic cavity
BUCKET HANDLE MOVEMENT : Elevation of ribs to increase lateral diameter of thoracic cavity
Muscles of Exhalation
Quiet Exhalation - passive :
-lung elastic recoil
-inspiratory muscles relax: diaphragm, external intercostals, ribs depress
Forceful Exhalation :
-contraction of internal intercostals
-pull ribs inferiorly
-contraction of abdominal muscles (rectus abdominis) because elastic recoil of lungs reinforced by contraction of the abdominal muscles so force abdominal contents against diaphragm, pushing it up
-increased pressure in abdominal region + thorax so air rushes out
Lung volume definitions
VT – tidal volume (varies with breathing pattern)
volume of air moved into or out of the lungs during quiet breathing
IRV – inspiratory reserve volume
- extra volume that can be inspired after breathing in tidal volume
- extra volume of lung you have if you want to take a deep breath (during exercise)
ERV – expiratory reserve volume
- extra volume that can be expired after breathing out tidal volume
- maximal volume of air that can be exhaled from the end-expiratory position
VC –vital capacity
*volume of air breathed out after maximal inhalation
RV – residual volume (can’t blow this out)
- volume of air remaining in lungs after maximal exhalation (VC)
- because you can’t collapse lungs anymore or push your ribcage down any further
FRC – Functional residual capacity
- volume in lungs after breathing out tidal volume (at the end of a normal breath out).
- it’s ERV + RV
TLC – Total lung volume
*volume in lungs at maximal inflation, sum of VC and RV.
Factors that Effect Air flow
Lung Compliance
Lung Resistance
Lung compliance
=ability of lungs to inflate
=ratio of change in lung volume : change in transpulmonary pressure
so alveolar pressure - intrapleural pressure
High compliance: easily expanded
Low compliance: resist expansion
Lung compliance = ΔV / ΔP
Is a feature of the small airways (alveoli)
Certain disease states alter lung compliance
Elastin compliance
-When lungs expand, elastin stretches
-Alveoli have elastin
Fibrosis: elastin replaced by collagen (fibrous) eg silicosis, asbestosis
-Emphysema (COPD) :
Breakdown of alveolar walls
Degraded elastin
HIGH compliance so easy for lungs to distend but they empty slowly so lungs become chronically over-inflated and have a reduced capacity to recoil
Compliance - Surfactant
- Lowers surface tension of water
- Prevents alveolar collapse : when diameter of alveoli decreases, surfactant molecules pack together so alveoli stabilised + don’t collapse
- When surfactant is reduced/absent : increased surface tension of fluid lining alveoli so decreased compliance
Airway resistance
Anything that decreases diameter increases airway resistance
eg :
-Oedema – vessels leak fluid
-Asthma – bronchoconstriction, mucus plugging, inflammatory oedema
-COPD (bronchitis) – pathological remodelling of the airway, mucus plugging
Unconscious Neural Control of Breathing
Respiratory pattern generator (RPG) within medulla – oscillator
Main players:
-Dorsal respiratory group = mainly inspiratory neurons for inspiration initiation
-Ventral respiratory group = in medulla, inspiratory and expiratory neurons for finishing inspiration and expiration, send impulses to phrenic + intercostal nerve supplying external intercostals
Muscle innervation of breathing
Phrenic nerve (C3-5) = diaphragm Phrenic nerve (T1-12) = intercostal nerves
Conscious Neural Control of Breathing
Cortical override
Control of breathing
Central chemoreceptors :
-Respond to changes in CSF pH
-In medulla
-Respond to changes in H+/HCO3- so indirectly detecting changes in [CO2]
Peripheral chemoreceptors :
-PO2, PCO2, pH
-In carotid bodies monitorppwithin arterial vessels
-Links to RPG via CN IX (glossopharyngeal nerve)
[aortic body, located onaortic arch, monitors [O2] closer toheart]
Drives of breathing
Hypercapnic drive - regular regulator of breathing :
-Increased CO2/H+ by hypoventilation –> acidosis
-Sensed by central + peripheral chemoreceptor
Hypoxic drive :
-Sensed by peripheral chemoreceptors
-Used when Low PaO2 (below 8kPa – normal =13)
Gas Exchange
- oxygen enters airways via inspiration -> alveolar sacs
- diffuses across alveolar membrane + pulmonary capillary endothelial cells, into blood
- transported to cells for respiration – oxidative phosphorylation.
- transported around body in blood by binding to Hb
- CO2 produced from cellular respiration
Conditions for maximal diffusion rate
1. High partial pressure gradient; Hypoventilation + hypoperfusion affect this 2. High SA Emphysema reduces SA 3. Short distance Fibrosis increases membrane thickness
Alveolar gas equation
PAO2 = F₁O2 x (PB - PH2O) - (PaCO2/RER)
F₁O2 : O2 content of inspired air
PB : 100kPa - sea level
PH2O : 6kPa - humidified air
PAO2 : alevolar content
F₁O2 x (PB - PH2O) : O2 inspired (19.74)
(PaCO2/RER) : O2 consumption
Bohr Effect
- increased partial pressure of oxygen –> increased oxyhaemoglobin saturation,
- Left shift = less partial pressure of oxygen required to saturate Hb eg increased pH, reduced 2-3 DPG
- Right shift = partial pressure of oxygen in more demand to saturate Hb so oxygen affinity less so you need increased 2-3 DPG + decreased pH
Numbers for lung
pH (7.35 - 7.45) PaO2 (10.6-13.3kPa) PaCO2 (4.9-6.1kPa) Nitrogen 79% Oxygen 21% Carbon dioxide 0.04%
Effect of hypoxia
Hypoventilation
Diffusion Defect
Shunt
V/Q mismatch
Hypoventilation from hypoxia
- Only cause of hypercapnia (high CO2) + hypoxemia caused by inability to exhale CO2 + inhale O2
- Low O2 / high CO2
- Causes: obesity, (difficult to expand chest), sleep apnoea (intermittent airway obstruction)
Diffusion Defect from hypoxia
Caused by changes in Ficks law eg SA, conc gradient
Seen in emphysema (COPD) and fibrosis
V/Q mismatch
- problems with ventilation or lung perfusion eg pulmonary emboli or obstruction of bronchi
- pulmonary vasoconstriction to divert blood away from this area of V/Q mismatch
- to become oxygenated.
- area in which it left, where there was V/Q mismatch is :
- ‘physiological dead space’.
- Supplemental oxygen can help
- Norm ventilation = 5L/min
Shunt from hypoxia
- FULL LUNG BLOCKAGE – perfusion without ventilation
- when perfusion without ventilation eg pneumonia
- deoxygenated blood leaving RHS of heart returns to LHS without being oxygenated
- Supplemental O2 WON’T help
- Low O2/ norm or high CO2
Respiratory failure
Type 1 : -Low PaO2 / normal PaCO2 -Caused by V/Q mismatch -Hypoxemia + normal CO2 -Although normal Pa02 range is 10.6-13.3kPa, not in respiratory failure until drops below 8 kPA. Type 2 : -Low PaO2 / high PaCO2 -Caused by full shunt -Hypoxemia + hypercapnia
Restrictive vs. Obstructive
Obstructive : -FEV1/FVC < 70% -COPD + asthma Restrictive : -FEV1/FVC > 80% -Interstitial lung disease where lung fibrosis
Haldane Effect
- venous blood carries more CO2 than arterial blood
- due to deoxyhaemoglobin having higher affinity for CO2 + H+ than oxyhaemoglobin
- as oxyhaemoglobin dissociated with oxygen by the time come into arterial blood from offloading at tissues
- then more deoxy Hb in venous blood
- Hb doesn’t saturate with CO2
- deoxyHb buffers pH so CO2 can dissolve in blood + bind to Hb
Asthma
=chronic, inflammatory obstructive disease
-Reversible airflow limitation + bronchial hyperresponsiveness
Symptoms :
wheezing, breathlessness, coughing, diurnal variation (so more prevalent either early morning or late at night)
Pathophysiology :
-Increased SM
-Alveolar oedema (due to inflammation where alveolar membrane more permeable)
-Increased goblet cells which limit airway flow + airway resistance
-Plasma leakage in alveoli
Can be split into extrinsic or intrinsic asthma :
Extrinsic: Known triggers
Intrinsic: No known triggers
COPD
Emphysema (loss of elastin in alveoli) Chronic inflammation Obstructive not Restrictive -Decreased ventilation – alveolar hypoxia -Decreased lung recoil – increased expiratory effort -Overall = hypoxaemia Treatment: Anti-mus β-agonists
