Electrolytes Flashcards
(154 cards)
1
Q
Describe the appearance of magnesium
A
Vial of clear colourless solution fo magnesium sulfate containing 2mmol/ml of ionic magnesium (50%)
2
Q
How can magnesium be adminsitered
A
Orally, nebulised, IV
3
Q
What salts can magnesium be prepared with?
A
Sulfate, chloride, hydroxide and aspartate
4
Q
How does magnesium act in the heart?
A
It increased uptake of intracellular calcium into the sarcoplasmic reticulum leading to relaxation and a lower RMP stabilising the membrane, reducing spontaneous depolarisations and slowing rate in conducting tissue
4
Q
What is magnesiums MOA
A
- Essential for the production of ATP, DNA, RNA and over 300 enzyme systems
- Dose dependent pre-synaptic inhibitino of ACh release at the NMJ leading to skeletal muscle relaxation
- It increased uptake of intracellular calcium into the sarcoplasmic reticulum leading to relaxation and a lower RMP stabilising the membrane, reducing spontaneous depolarisations and slowing rate in conducting tissue
- CNS depressant effects vai post synaptic inhibitino of NMDA receptors (non competitive)
- Cofactor in electrolyte homeostasis through its role in Na/K ATPase function
4
Q
Effect of IV magnesium cardiovascularly
A
Peripherla vasodilation, bradycardia with slowed sinus node impulse formation, prolonged conduction time in AV node and through conductive tissue, prolonged refractory periods and attentuates vasoconstriction and arrhythmogenesis from adrenaline
5
Q
What effect does magnesium have on the lung
A
Bronchodilator
Attenuates hypoxic pulmonary vasoconstriction
In toxic dopses causes respriatory failure
6
Q
What effects does magnesium have outside the lung and heart
A
- CNS
CNS depressant - enhances other CNS depressant action
Anticonvulsant propoerties
High concentration inhibit catecholamine release from adrenergic nerve termianls
Prolongs NMB - Renal - vasodilation and diuretic
- Gut - osmotic laxative
- Obstetric - decreased uterine tone and contracitlity, increased placental perfusion
- Haem - prolongs clotting time and decreases thromboxane A2 synthesis inhibiting thrombin iinduced platelet aggregation
7
Q
Magnesium affects the action of what other drugs
A
Neuromuscular blockade prolonged
Enhances the action of other sedatives
8
Q
Magnesium half life IV
A
4 hours
9
Q
Magnesium absorption orally
A
25-65% varying depending on systemic Mg levels
10
Q
Magnesium protein binding
A
30%
11
Q
Magnesium Vd
A
0.3L/kg
12
Q
Magnesium excretion?
A
50% of exogenous magneisum load excreted in the urine even in deficiency
Reabsorption mainly via thick ascending limb and DCT
13
Q
What is total body sodium content
A
50mmol/kg
* 60mmol/kg Na –> 70kg male has 4200mmol or 92g of which 70% is exchangeable and 50% of total body sodium is in ECF (5% in ICF), 45% in boneW
14
Q
Where is sodium kept in the body? How much is accessable
A
- 60mmol/kg Na –> 70kg male has 4200mmol or 92g of which 70% is exchangeable and 50% of total body sodium is in ECF (5% in ICF), 45% in bone
15
Q
What % of sodium content is in the ECF?
A
50%
16
Q
What % of sodium content is in bone
A
45%
17
Q
Is serum or plasma sodium higher?
A
- When plasma sodium is measured it is similar to intersitital fluid but by measuring it without plasma solids (protein) you remove the gibbs donnan effect (Na in total volume 140mmol/L, but in WATER volume is 147mmmol/L, while 140mmol in interstitial fluid and 12mmol/L in cells)
◦ Low in cells due to Na/K pump and low permeability - Can be measured using Na isotope
18
Q
How does plasma sodium compare to intersitial fluid sodium
A
- When plasma sodium is measured it is similar to intersitital fluid but by measuring it without plasma solids (protein) you remove the gibbs donnan effect (Na in total volume 140mmol/L, but in WATER volume is 147mmmol/L, while 140mmol in interstitial fluid and 12mmol/L in cells)
◦ Low in cells due to Na/K pump and low permeability - Can be measured using Na isotope
19
Q
What is the concentration of Na in cells?
A
12mmol/L
20
Q
Daily intake of Na
A
50-100mmol/day
21
Q
Absorption of sodium occurs via?
A
◦ Glucose-coupled - nutrient coupled absorption - especially in jejenum (AT2 upregulates)
◦ Na+/H+ exchange accounts for most of the intestinal absorption in the ileum (AT2 upregulates)
‣ H+ is then used to drive CL/HCO3 exchange to absorb chloride
◦ ENaC in the colon apical membrane - Aldosterone regulates colonic absorption to some minor extent`
22
Q
How much sodium ends up in the stool per day?
A
- Total stool content 30 mmol/L, = only 3mmol/day is excreted in this way (i.e. almost 100% of dietary sodium is absorbed)
23
How is the extracellular vs intracellular sodium balance maintained?
* Cellular membranes have very poor sodium permeability and therefore no avenue to adjust extracellular sodium by movement in and out fo cells, only by elinination of Na and intake of H20
* Na+/K+ ATPase maintains high extracellular (135-145 mmol/L) and low intracellular concentration (10-15 mmol/L)
24
Where can sodium be sequestered
Sodium sequestration in skin and connective tissue
* Bound to negatively charged residues on glycosaminoglycans
* Not osomotically active
* Serves as a buffer to prevent haemodynamic changes from dietary sodium fluctuations
25
What is the main mechanism of sodium regulation?
Renal
Mainly distal nephron
26
What happens to sodium in the proximal neprhon
◦ Sodium is freely filtered
◦ 65% reabsorbed in PCT
‣ Driven by concentration gradient perpetuated by basolateral Na/K ATPase, with most of the Na reabsorbed by antiport with hydrogen and cotransport with glucose/amino acids
◦ None is reabsorbed in thin descending, and minimal in thin ascending
◦ 25% reabsorbed in thick ascending limb - furosemide sensitive NKCC2 cotransporter
27
What happens to sodium in the distal tubule?
◦ 5-10% by thiazide sensitive NCC cotransporter - load sensitive - reasborption increases when increased Na delivered
◦ 2% in collecting duct - passive and amiloride sensitive ENaC channel
28
What 5 factors specifically alter sodium reabsorption
◦ GFR manipulation by adrenaline/SNS input and Angiotensin 2 reduces GFR and reduces Na filtration and therefore potential loss
◦ Angiotensin II (increases reabsorption by increasing Na+/K+ ATPase activity in the proximal tubule, and increases NHE3 activity)
◦ Aldosterone (increases ENaC activation in the collecting duct and Na+/K+ ATPase activity in the thick ascending limb)
◦ Vasopressin (increases expression of ENaC in the collecting duct and NKCC2 in the thick ascending limb) - also regulating its concentration through water reabsorption
◦ Catecholamines by increasing NKCC2 expression in the thick ascending limb
29
What 4 reasons might sodium losses be increased in the ICU
* Sweat (in the unacclimatised, sweat contains up to 60mmol/L of sodium) with theoretical sweating of up to 12L per day (720mmol/day Na loss)
* NG drainage (erratic, 10-120 mmol/L)
* Ileostomy output (~120 mmol/L)
* Wound drain, pleural drain, burns (same as normal ECF, 135-145 mmol/L)
30
What is the plasma solids effect?
* Na in plasma 140 --> Na in interstitial fluid 140mmol/L
* Plasma water 93%, plasma solids 7% (proteins) --> Na content in plasma WATER is higher than interstitial fluid by 6-7mmol/L BUT if measured as though in the whole plasma the same
* i.e. measured concentration of Na is lower than actual plasma water concentration
* Then why if Na rises 6-7mmols/L does this only contribute 0.4mmols/L to oncotic pressure?
◦ Other electrolytes balance this out --> Cl concentration lower
◦ This means that the apparent protein concentration goes from 0.9mosm/L to 1.3mosmol/L
31
How much K is there in the body?
* 40mmol/kg of this 90% intracellulalr- extracelllularly is 2% and 8% in bone
◦ Intracellular concentration varies depending on cell type 120-150mmol/L, intravascular and intersitial 3.5-5 mmol/L equilibrating freely between these leaving 50-75mmol in extracellular fluid
32
Where is total body K distributed between?
* 40mmol/kg of this 90% intracellulalr- extracelllularly is 2% and 8% in bone
◦ Intracellular concentration varies depending on cell type 120-150mmol/L, intravascular and intersitial 3.5-5 mmol/L equilibrating freely between these leaving 50-75mmol in extracellular fluid
33
What is the intracellualr concentration of K
* 40mmol/kg of this 90% intracellulalr- extracelllularly is 2% and 8% in bone
◦ Intracellular concentration varies depending on cell type 120-150mmol/L, intravascular and intersitial 3.5-5 mmol/L equilibrating freely between these leaving 50-75mmol in extracellular fluid
34
How is K content measured?
* K content can be measured using K44 isotope which is of fixed proportion in the body - exchangeable K can be measured using radioactive K42 isotope
35
What is the role of K
* Maintenance of intracellular fluid tonicity / regulation of cell volume
* Maintenenance of resting membrane potential
◦ Responsible for the excitability of excitable tissues, action potentials etc
* Structural function (incorporated into bone, ribosomes, DNA and RNA)
* Intracellular and extracellular messenger function (mediator of nociception, inflammation, vasodilation)
36
What is the daily intake of K? How is it absorbed?
* Intake is not regulated (passive paracellular gut absorption) - although 75mmol/L lost in faeces (of100ml). Passive paracellular diffusion via concentration gradient
◦ Daily intake 70mmol/day
37
How is K eliminated?
* Renal elimination is 95% of the total daily potassium excretion.
◦ 50-60% passively reabsorbed in proximal tubule, 30% reabsorbed in thick ascending tubule NKCC2 cotransporter and K is secreted in the distal tubular lumen
◦ Minimum urinary potassium is 5mmol/LK
38
How is potassium increased oral K regulated?
* Oral potassium intake
◦ Produces immediate kaliuresis; intestinal K+sensor is implicated
* High potassium intake: leads to the increased expression of ROMK channels - takes time to develop
39
What happens to potassium with increased renal sodium delivery?
* High distal sodium delivery: compensatory increase in potassium secretion to maintain electroneutrality.
40
What is the effect of aldosterone on K
* Aldosterone
◦ Increases renal elimination by increasing the activity of ENaC channels in the nephron
◦ Increases GI elimination in colon (5% of total)
◦ Aldosterone increases the activity of Na+/K+ ATPase pumps in skeletal muscle and its activity in the distal tubule/collecting duct promotes potassium excretion (it is released in response to hyperkalaemia)
41
What effect does plasma acid base have on potassium?
* Acid-base disturbances: metabolic acidosis causes distal potassium secretion to decrease with increased K/H exchange in intercalated cells
42
What effect does hydration have on potassium?
* hydration - systemic release of vasopressin, increasing ROMK channels on principal cels and NKCC2 transporter in thick ascending limb
43
How does insulin affect plasma K
◦ Insulin by the insertion of extra Na+/K+ ATPase pumps into the membrane, thus increased cellular potassium uptake
‣ Increases phosphorulation of insulin receptor substrate protein activating protein kinase C
44
How do catecholamine affect potassium
◦ Catecholamines increase the activity Na+/K+ ATPase pumps - specifically beta agonists (Beta 2)
45
Why does plasma pottasium rise more in some instances of Succinylcholnie use and not others?
◦ NMJ --> Nonspecific cation channels eg. acetylcholine-gated sodium channels in the neuromuscular junction are capable of leaking potassium out of the cell
‣ become more numerous in stroke, spinal injury, denervation so depolarisation muscle relaxants cause large rise in K
46
Why does K move in acid base?
◦ Acid-base changes effectively produce H+/K+ exchange across the membrane, i.e. metabolic acidosis produces a movement of potassium into the ECF
‣ Mediated by H+/Na exchanger in skeletal muscle decreasing activity in acidosis, resulting in reduced action of Na/K ATPase; and K leaky channels still present
47
What effect does energy availability have on potassium movement across cell membranes and therefore systemic K?
◦ ATP sensitive K channels - nucleotide sensitive cation channels in smooth muscle, cardiac muscle, skeletal muscle, pancreas
‣ Open in the absence of ATP, decreasing RMP --> K increased into extracellular fluid
‣ Closure promoted by high glucose, and opened by glucagon
‣ Nicorandil opens these channels, and sulfonylureas close them
48
What are the ECG changes of hyperkalaemia?
ECG changes of hyperkalemia: - Hyperexcitability initiailly with decreased RMP --> then reduced conduction velocity with inactivation of Na channels
* Tall peaked T waves with a narrow base
* Shortened QT interval
* ST-segment depression
* P wave widening/flattening, PR prolongation
* Sinus bradycardia, high-grade AV block
* Conduction blocks (bundle branch block, fascicular blocks)
* QRS widening with bizarre QRS morphology
49
How does rehydration affect plasma potassium?
* Rehydration (i.e. IV fluids)
◦ Dosing: 1000-2000ml
◦ Mechanism: dilution; support of diuresis
◦ Time to onset: minutes
◦ Duration of action: hours
50
How does bicarbonate affect plasma K
* Intracellular movement (temporary) Bicarbonate (esp. isotonic bicarbonate)
◦ Dosing: 100-200mmol
◦ Mechanism: H+/K+ exchange, using the Na+/K+ ATPase. Restores transmembrane gradient
◦ Time to onset: minutes
◦ Duration of action: 1-2hours
51
How do beta agonists affect plasma K
◦ Mechanism: increase the activity Na+/K+ ATPase pumps
◦ Dosing: 5mg nebulised salbutamol
◦ Time to onset: minutes
◦ Duration of action: hours
52
How does insulin affect plasma K
◦ Dosing: 10-50 units, administered with dextrose
◦ Mechanism: the insertion of extra Na+/K+ ATPase pumps into cell membranes, thus increased cellular potassium uptake
◦ Time to onset: seconds/minutes - max effect at 30 minutes
◦ Duration of action: 2-3 hours
◦ Removal via the urine
53
How does furosemide affect plasma K
◦ Mechanism: increased sodium delivery to the distal nephron; exchange of sodium for potassium, and thus kaliuresis
◦ Dosing: 40-80mg
◦ Time to onset: 20-40 minutes
◦ Duration of action: hours
54
How does resonium affect plasma K
◦ Cation exchange resin - resonium
◦ Mechanism: binding of potassium into the resin in exchange for another cation (eg. calcium or sodium) --> 1mmol of K for 1mmol of Na for every g of resin
◦ Dosing: 10-50g
◦ Time to onset: hours - oral slower than rectal as exchange in colon.
◦ Duration of action: hours
55
What is the baselien amount of magnesium in the body?
* 15mmol/kg in the body ~1000mmol in 70kg body
◦ 60% in bone
◦ 39% intracelluarly (10mmol/L) - bound to ATP, cell wall lipids (membrane stabiliser) and enzymes
◦ 1% extracellular. 10mmol total in ECF
‣ Intracellular magnesium enters cells freely and bound to ATP, cell wall lipids and enzymes
‣ Mangesium equilibrates freely between ECF
‣ 0.7-1mmol/L
56
Where is magnesium distributed in the body?
* 15mmol/kg in the body ~1000mmol in 70kg body
◦ 60% in bone
◦ 39% intracelluarly (10mmol/L) - bound to ATP, cell wall lipids (membrane stabiliser) and enzymes
◦ 1% extracellular. 10mmol total in ECF
‣ Intracellular magnesium enters cells freely and bound to ATP, cell wall lipids and enzymes
‣ Mangesium equilibrates freely between ECF
‣ 0.7-1mmol/L
57
What % of magnesium is extraceullar?
* 15mmol/kg in the body ~1000mmol in 70kg body
◦ 60% in bone
◦ 39% intracelluarly (10mmol/L) - bound to ATP, cell wall lipids (membrane stabiliser) and enzymes
◦ 1% extracellular. 10mmol total in ECF
‣ Intracellular magnesium enters cells freely and bound to ATP, cell wall lipids and enzymes
‣ Mangesium equilibrates freely between ECF
‣ 0.7-1mmol/L
58
In what state is serum magnesium?
◦ 40% protein bound
◦ 5-10% is complexed with phosphate lactate citrate, just like calcium
◦ 50-55% is available as free biologically active ion.
59
Describe the fate of dietary magnesium?
◦ 30% of dietary magnesium is absorbed in the intestine
◦ 90% passive concentration dependent paracellular absorption; 10% saturable active transport in jejenum/ileum
◦ More is absorbed in states of magnesium depletion
60
How is magnesium regulated between its sites of storage?
◦ Intracellular pool is tightly regulated - although its entry into cells does not require active transport
◦ Extracellular magnesium is exchanged mainly with bone - slow process, hypomagnesaemia depresses PTH secretion and impairs tissue response
61
How is magnesium handled in the kidney?
◦ Free magnesium ions are ultrafiltered at the glomerulus
◦ 10–15% of the filtered magnesium is reabsorbed in the proximal tubule
◦ 60–70% is reabsorbed in the thick ascending limb of the loop of Henle
◦ 10-15% is reabsorbed in the distal convoluted tubule
◦ DCT process is actively regulated by plasma Mg2+ concentration; reabsorption is near-total at normal magnesium levels, and decreases in hypermagnesemia
◦ 3% of filtered magnesium is excreted
62
What % of magnesium filtered is excreted?
◦ Free magnesium ions are ultrafiltered at the glomerulus
◦ 10–15% of the filtered magnesium is reabsorbed in the proximal tubule
◦ 60–70% is reabsorbed in the thick ascending limb of the loop of Henle
◦ 10-15% is reabsorbed in the distal convoluted tubule
◦ DCT process is actively regulated by plasma Mg2+ concentration; reabsorption is near-total at normal magnesium levels, and decreases in hypermagnesemia
◦ 3% of filtered magnesium is excreted
63
What part of magensium handling in the kidney is regulated?
◦ Free magnesium ions are ultrafiltered at the glomerulus
◦ 10–15% of the filtered magnesium is reabsorbed in the proximal tubule
◦ 60–70% is reabsorbed in the thick ascending limb of the loop of Henle
◦ 10-15% is reabsorbed in the distal convoluted tubule
◦ DCT process is actively regulated by plasma Mg2+ concentration; reabsorption is near-total at normal magnesium levels, and decreases in hypermagnesemia
◦ 3% of filtered magnesium is excreted
64
What are the overall functions of magnesium
◦ Enzyme function: membrane-bound ATPases, kinases, alk phos., enolase
‣ Catalyst or activates over 300 separate enzymes esp. all involving phosphate transfer, for sodium pump, oxidative phosphorylation and all ATP reactions
◦ Membrane function: cell adhesion, Transmembrane electrolyte flux
◦ Structural function: protein folding, polyribosomes, nucleic acids
◦ Muscles:
‣ vasodilation/relaxation of smooth muscle via Calcium channel antagonism
‣ Reduced membrane excitability
‣ Reduced neurotransmitter release at NMJ - potentiate NMJ blockers
◦ Nerves
‣ neurotransmitter release (NMDA blocker)
‣ Slow action potential conduction
◦ Bone metabolism (affects the function of parathyroid hormone)
65
Describe the effects of hypermagnesaemia?
* 0.7 - 1 normal
* 2 - 3.5 therapeutic range for toxaemia
* >2.5 ECG changes - increased PQ, wide QRS
* >4 symptoms
* >5 loss of patella reflex
* 6-8 respiratory paralysis
* 7.5 complete heart block
* 12 asystole
66
How is magnesium affected by the Gibbs Donnan effect?
* Ions protein bound so only concentration of free ion used so Gibbs Donnan cofactor is 0.9 (whereas for sodium 0.5 and for anions 1.05)
67
How much calcium is there in the body?
* 360mmol/kg of Ca in the body - 70kg male has 1000g
◦ 99% in bone
‣ 12.5mmol is exchanged between bone and ECF over a 24 hour period.
◦ 30mmol in ECF (2.4mmol/kg),
‣ 7mmol in circulating blood.
68
How much calcium is kept intracellualrly?
◦ 99% in bone
‣ 12.5mmol is exchanged between bone and ECF over a 24 hour period.
◦ 30mmol in ECF (2.4mmol/kg),
‣ 7mmol in circulating blood.
* None intracellularly as extruded by ATP powered pumps as it is a potent secondary messenger
69
Where is body calcium stored/distributed?
◦ 99% in bone
‣ 12.5mmol is exchanged between bone and ECF over a 24 hour period.
◦ 30mmol in ECF (2.4mmol/kg),
‣ 7mmol in circulating blood.
* None intracellularly as extruded by ATP powered pumps as it is a potent secondary messenger
70
How is Calcium distrbuted in the ECF
◦ 15% bound to anions - lactate, sulfate, phosphate
◦ 40% bound to albumin
◦ 45% ionised free fraction
71
What roles does calcium have in the body?
* Structure - Component of the hydroxyapatite matrix
* Functional roles
◦ Intracellular second messenger, essential to:
‣ Skeletal and smooth muscle contraction/relaxation
‣ presynaptic release of neurotransmitter
‣ endocrine/exocrine hormone secretion
‣ apoptosis
‣ mitochondrial energy production
‣ Cell proliferation
‣ Cytoskeletal changes which precede phagocytosis
* Autocrine and paracrine extracellular messenger
* Co-factor in extracellular enzymatic reactions:
◦ Clotting cascade
72
What are the differences between calcium chloride and calcium gluconate?
* Pharmaceutics
◦ calcium chloride is a more concentrated (6.8 mmol/L)
‣ Faster to make up an infusion
‣ Less instrumentation of ampoules is protective against infection and decreases the risk of drug error.
* Chemical properties:
◦ Calcium chloride: 2040 mOsm/kg, pH 5.5-7.5 (lower pH)
‣ 1g of calcium chloride per vial - 6.8mmol Ca, 13.6mmol Cl (Cl lighter than gluconate)
◦ Calcium gluconate: 680 mOsm/kg, pH 6.0-8.2
‣ 1g of calcium gluconate per 10ml - each Ca is bound to 2x gluconate ions
* Irritant properties:
◦ Calcium chloride is thought to be more irritant than gluconate
◦ Both are listed as noncytotoxic vesicants (both receive a "RED" rating)
73
How much calcium is absorbed per day?
* Net absorption 3.75mmol per day (7.5mmol reabsorbed and 3.75mmol lost in gut)
74
How is calcium absorbed?
* Duodenal and ileal (most) absorption via active transcellular process
◦ Apical entry via epithelial calcium channels (TRPV5) divalent cation channels (Mg as well)
◦ Diffusion along cell bound by calbindin to avoid secondary messenger activity
◦ Extrusion into bloodstream via basal Ca ATPase (80% of work) and Na/Ca exchange protein (NCX1) both using ATP (secondary active transport in case of Na/Ca exchange protein)
* Paracellular passive uptake - primary route if adequate calcium within body
* Modulation
◦ Both apical entry and intracellular diffusion protein production dependent on calcitriol/Vitamin D (PTH effects by increasing Vit D production in kidney; calcitonin antagonises this step)
75
How is gut calcium absorption modulated?
* Duodenal and ileal (most) absorption via active transcellular process
◦ Apical entry via epithelial calcium channels (TRPV5) divalent cation channels (Mg as well)
◦ Diffusion along cell bound by calbindin to avoid secondary messenger activity
◦ Extrusion into bloodstream via basal Ca ATPase (80% of work) and Na/Ca exchange protein (NCX1) both using ATP (secondary active transport in case of Na/Ca exchange protein)
* Paracellular passive uptake - primary route if adequate calcium within body
* Modulation
◦ Both apical entry and intracellular diffusion protein production dependent on calcitriol/Vitamin D (PTH effects by increasing Vit D production in kidney; calcitonin antagonises this step)
76
How does most calcium absorption occur?
* Duodenal and ileal (most) absorption via active transcellular process
◦ Apical entry via epithelial calcium channels (TRPV5) divalent cation channels (Mg as well)
◦ Diffusion along cell bound by calbindin to avoid secondary messenger activity
◦ Extrusion into bloodstream via basal Ca ATPase (80% of work) and Na/Ca exchange protein (NCX1) both using ATP (secondary active transport in case of Na/Ca exchange protein)
* Paracellular passive uptake - primary route if adequate calcium within body
* Modulation
◦ Both apical entry and intracellular diffusion protein production dependent on calcitriol/Vitamin D (PTH effects by increasing Vit D production in kidney; calcitonin antagonises this step)
77
What factors contribute to changing ionised calcium in the context of a stable total body calcium
* Increased albumin = decreased ionised calcium
* Increased ionic store reducing ionised calcium
◦ Higher pH/higher bicarbonate
◦ Increased lactate
◦ Phosphate increasing
◦ Citrate increasing
* Heparin decreased ionised Ca
* FFA decrease ionised Ca
78
WHat is the normal bony turnover of calcium per day
Daily flux in and out 12mmol
79
What hormones regulate movement of calcium in and out of bone? How do they do this?
* Calcitonin - inhibits osteoclasts via GPCR de-acidifying the resorptive surface (decreasing Ca availability from the bone pool)
* PTH - primarily through ostoeblast activtiy with secondary indirect osteoclast action it increases bone resorption, reduced bone synthesis increasing Ca availability
* Calcitriol - stimulates osteoclastic bone resorption, but protective against osteoporosis
80
How much calcium is lost in the gut per day? Why?
* Gut - 50% of absorption is subsequently lost back into the gut each day
◦ Unabsorbed, excreted in digestive enzymes, shed in gut mucosa and subsequently bound to dietary phosphate rendering it insoluble
81
Describe the renal processing of Ca
* Renal - Although 99.8% of calcium filtered is reabsorbed in the kidneys 3.75mmol is excreted (similar amount to gut)
◦ 70% is reabsorbed in the proximal tubule
◦ 20% is reabsorbed in the thick ascending limb - autoregulated by calcium sensing receptor in basolateral membrane of thick ascending limb
◦ 10% is reabsorbed in the distal convoluted tubule transcelluarly by
‣ Apical transport protein TRPV5/6
‣ Calbindin transports through cell
‣ Ca ATPase extrudes on basolateral membrane
82
Describe the reabsorption of Ca in the kidney
* Renal - Although 99.8% of calcium filtered is reabsorbed in the kidneys 3.75mmol is excreted (similar amount to gut)
◦ 70% is reabsorbed in the proximal tubule
◦ 20% is reabsorbed in the thick ascending limb - autoregulated by calcium sensing receptor in basolateral membrane of thick ascending limb
◦ 10% is reabsorbed in the distal convoluted tubule transcelluarly by
‣ Apical transport protein TRPV5/6
‣ Calbindin transports through cell
‣ Ca ATPase extrudes on basolateral membrane
83
How much Ca is excreted per day in the kidney?
* Renal - Although 99.8% of calcium filtered is reabsorbed in the kidneys 3.75mmol is excreted (similar amount to gut)
◦ 70% is reabsorbed in the proximal tubule
◦ 20% is reabsorbed in the thick ascending limb - autoregulated by calcium sensing receptor in basolateral membrane of thick ascending limb
◦ 10% is reabsorbed in the distal convoluted tubule transcelluarly by
‣ Apical transport protein TRPV5/6
‣ Calbindin transports through cell
‣ Ca ATPase extrudes on basolateral membrane
84
How is Ca reabsorption in the kidney regulated?
◦ Regulated by PTH calcitriol and calcitonin:
‣ Calcitonin decreases the reabsorption of calcium and phosphate at basolateral membrane ATPase
‣ PTH and calcitriol increase the reabsorption of calcium and phosphate at apical membrane by increasing transcription and apical membrane insertion of TRPV5 and increased calbindin
‣ Calcitriol increases the activity of calbindin, TRPV5 and TRP
85
Describe the MOA of bisphosphanates
* Analogues of pyrophosphate inhibiting osteoclast and osteoblast activity
◦ Osteoclast - binding to bone apatite crystals and local release during resorption accumulating under osteoclasts inhibiting recruitemnt and adhesion, shortening life span (metabolised into toxic ATP analogue) and inhibiting osteoclast activity
◦ Inhibit calcification by inhibiting formation of calcium phosphate salts
‣ Bind to calcium of calcium phosphate inhibiting the formation and aggregation of calcium phosphate crystals and therefore formation of hydroxyapatitie reducing mineralisation of normal bone
86
What type of hormone is PTH?
Polypeptide secreted from chief cells in the parathyroid gland
87
Where is PTH secreted from? How is the requirement for PTH release sensed? What cell type releases it? What type of hormone is it?
* PTH is a polypeptide hormone secreted by the parathyroid glands
◦ From chief cells in parathyroid gland
◦ Calcium sensing via membrane receptor
88
WHat stimulates PTH release
Hypocalcaemia
hyperphosphataemia
89
What inhibits PTH release
‣ calcitriol
‣ Hypercalcaemia
‣ Vitamin D
‣ hypermagnesemia
‣ Cytokines
‣ PG
90
PTH acts at what receptors? Leads to?
◦ MOA - G protein coupled receptors
◦ Actions: increases plasma calcium by
‣ Increasing its renal reabsorption at PCT
‣ Increased osteoclast activity, decreased osteoblast
‣ Also increases Vit D conversion into calcitriol in the kidney increasing absorption
91
Calcitriol is?
* Calcitriol is the metabolic product of Vit D, a fat-soluble vitamin (1, 25 dihydroxycholecalciferol (STERIOD hormone)
92
How is Calcitriol made
◦ Production - UV light on cholesterol precursers then hydrolysed by the liver then kidney
93
What is the stimulus for calcitriol release?
‣ hypocalcemia
‣ hyperphosphatemia
‣ PTH
94
What inhibits calcitriol release
‣ decreased sun exposure
‣ decreased functional renal mass,
‣ elevated calcium and phosphate levels
95
What receptors does vitamin D act on?
Nuclear receptors affecting transcription factors
96
What are the actions of calcitriol?
◦ Actions: increases plasma calcium by
‣ increasing its gut absorption
‣ Increasing renal reabsorption at PCT
‣ Inhibits the production of PTH; conflicting effects on osteoclast activity
97
What is calcitonin? Where does it come from?
* Calcitonin is a polypeptide hormone secreted from parafollicular cells of the thyroid
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What stimulates the release of calcitonin?
◦ Stimulus for release: hypercalcemia, gastrin
99
What inhibits the release of calcitonin?
Hypocalcaemia
Somatostatin
100
What is the MOA of calcitonin?
GPCR receptor
101
Actions of calcitonin?
◦ Actions: decreases plasma calcium by
‣ Decreasing its renal reabsorption at PCT
‣ Inhibiting osteoclast activity - decreasing bone resorption
‣ Increased calcitriol syntheiss in the kidney indirectly increasing absorption
102
How much chloride is there in the body?
45mmol/kg
115g in a 70kg body
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Where is chloride distributed in the body?
◦ 90% extracellular contirbuting 70% of anionic charge in ECF
◦ 100mmol/L in ECF - slightly higher in interstitial fluid than intravascular due to Gibbs Doonan effect
◦ Only 10mmol/L concentration intracelluarly and kept low by Cl/K cotransporter
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What is the concentration of bicarbonate in the cell
* 70% as carbonic acid where bicarbonate is the conjugate base
* 60% of free bicarbonate ions in extracellular fluid, and 50% of the total is in the functional ECF
* 10mmol/L intracellular concentration
* 24mmol/L intravascular; 28mmol/L inttersitital concentrations
◦ Freely moves between compartments - Gibbs Doonan effect accounts for different concentrations
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What is the concentration of bicarbonate in the plasma vs in the interstitium?
* 70% as carbonic acid where bicarbonate is the conjugate base
* 60% of free bicarbonate ions in extracellular fluid, and 50% of the total is in the functional ECF
* 10mmol/L intracellular concentration
* 24mmol/L intravascular; 28mmol/L inttersitital concentrations
◦ Freely moves between compartments - Gibbs Doonan effect accounts for different concentrations
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How is bicarbonate distributed?
* 70% as carbonic acid where bicarbonate is the conjugate base
* 60% of free bicarbonate ions in extracellular fluid, and 50% of the total is in the functional ECF
* 10mmol/L intracellular concentration
* 24mmol/L intravascular; 28mmol/L inttersitital concentrations
◦ Freely moves between compartments - Gibbs Doonan effect accounts for different concentrations
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How is lactate distributed?
* ECF 1.2mmol/L and equlibrates easily between intravascular and interstitial compartments
* ICF 1.5mmol/L - easily moving in and out of cells esp. muscles
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How much phosphate is there in the body?
* 320mmol/kg of phosphorous - 700g in an adult 70kg male
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How is body phosphate distirbuted?
* 85% in hydroxyapatite of bone
* 15% dissolved largely as phosphate anion (most as HPO42- 80% and H2PO4 20% - pKa 2.2, 7.2, 12.4)
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Of body phosphate that is not in bone in what state is most?
* 85% in hydroxyapatite of bone
* 15% dissolved largely as phosphate anion (most as HPO42- 80% and H2PO4 20% - pKa 2.2, 7.2, 12.4)
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Of the body phosophate not in bone how is it distributed?
* 15% dissolved largely as phosphate anion (most as HPO42- 80% and H2PO4 20% - pKa 2.2, 7.2, 12.4)
* 85% in hydroxyapatite of bone
* 15% dissolved largely as phosphate anion (most as HPO42- 80% and H2PO4 20% - pKa 2.2, 7.2, 12.4)
◦ 14.99% intracellular - concentration between 60-100mmol/L with 10mmol/L free
‣ Most abundant intracellular anion and an important buffer
‣ That which is not free is bound to phosphocreatinine, ATP/GTP/ADP, hexose phosphate
‣ Kept intracellular by Na/phopshate cotransport (insulin upregulates same)
◦ 12mmol in extracellular fluid at 1mmol/L
‣ Equilibrates easily between intravascular and interstitial fluid as HPO4- (80%),
‣ Exchanges with bone and intracellular phosphate
‣ In plasma
* 15% bound to protein,
* 45% free ionised,
* 40% complexed with Ca/Mg
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What concentration is intracellular phosphate
* 85% in hydroxyapatite of bone
* 15% dissolved largely as phosphate anion (most as HPO42- 80% and H2PO4 20% - pKa 2.2, 7.2, 12.4)
◦ 14.99% intracellular - concentration between 60-100mmol/L with 10mmol/L free
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What is the purpose of intracellular phosphate?
* 85% in hydroxyapatite of bone
* 15% dissolved largely as phosphate anion (most as HPO42- 80% and H2PO4 20% - pKa 2.2, 7.2, 12.4)
◦ 14.99% intracellular - concentration between 60-100mmol/L with 10mmol/L free
‣ Most abundant intracellular anion and an important buffer
‣ That which is not free is bound to phosphocreatinine, ATP/GTP/ADP, hexose phosphate
‣ Kept intracellular by Na/phopshate cotransport (insulin upregulates same)
◦ 12mmol in extracellular fluid at 1mmol/L
‣ Equilibrates easily between intravascular and interstitial fluid as HPO4- (80%),
‣ Exchanges with bone and intracellular phosphate
‣ In plasma
* 15% bound to protein,
* 45% free ionised,
* 40% complexed with Ca/Mg
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Extracellular phospahte concentration? Distribution
* 85% in hydroxyapatite of bone
* 15% dissolved largely as phosphate anion (most as HPO42- 80% and H2PO4 20% - pKa 2.2, 7.2, 12.4)
◦ 14.99% intracellular - concentration between 60-100mmol/L with 10mmol/L free
‣ Most abundant intracellular anion and an important buffer
‣ That which is not free is bound to phosphocreatinine, ATP/GTP/ADP, hexose phosphate
‣ Kept intracellular by Na/phopshate cotransport (insulin upregulates same)
◦ 12mmol in extracellular fluid at 1mmol/L
‣ Equilibrates easily between intravascular and interstitial fluid as HPO4- (80%),
‣ Exchanges with bone and intracellular phosphate
‣ In plasma
* 15% bound to protein,
* 45% free ionised,
* 40% complexed with Ca/Mg
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What state is extracellulkar phosphate in
◦ 12mmol in extracellular fluid at 1mmol/L
‣ Equilibrates easily between intravascular and interstitial fluid as HPO4- (80%),
‣ Exchanges with bone and intracellular phosphate
‣ In plasma
* 15% bound to protein,
* 45% free ionised,
* 40% complexed with Ca/Mg
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What is the purpose of intracellular phosphate?
* 85% in hydroxyapatite of bone
* 15% dissolved largely as phosphate anion (most as HPO42- 80% and H2PO4 20% - pKa 2.2, 7.2, 12.4)
◦ 14.99% intracellular - concentration between 60-100mmol/L with 10mmol/L free
‣ Most abundant intracellular anion and an important buffer
‣ That which is not free is bound to phosphocreatinine, ATP/GTP/ADP, hexose phosphate
‣ Kept intracellular by Na/phopshate cotransport (insulin upregulates same)
◦ 12mmol in extracellular fluid at 1mmol/L
‣ Equilibrates easily between intravascular and interstitial fluid as HPO4- (80%),
‣ Exchanges with bone and intracellular phosphate
‣ In plasma
* 15% bound to protein,
* 45% free ionised,
* 40% complexed with Ca/Mg
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What is daily dietary intake of phosphate>
* 40mmol/day is normal oral intake; plus another 5mmol/day is generated in the metabolism of phospholipids and proteins --> of this 25-30mmol/day is absorbed
* Absorbed in the intestine by passive and active mechanisms:
◦ Passive mechanism is paracellular
◦ Active mechanism is co-transport with sodium, and is regulated
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How is dietary phsophate absorbed
* 40mmol/day is normal oral intake; plus another 5mmol/day is generated in the metabolism of phospholipids and proteins --> of this 25-30mmol/day is absorbed
* Absorbed in the intestine by passive and active mechanisms:
◦ Passive mechanism is paracellular
◦ Active mechanism is co-transport with sodium, and is regulated
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Describe the renal handling of phsopahet?
* Total daily phosphate loss: 30mmol excreted renally, 15mmol via stool.
* Most of is reabsorbed in the proximal (70%) and distal (10-20%) tubules
◦ Freely filtered form that which is not protein bound
◦ Sodium phosphate cotransporter driven by Na gradient (transporters influenced by acid/base status of filtrate)
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Daily loss of phosphate
* Total daily phosphate loss: 30mmol excreted renally, 15mmol via stool.
* Most of is reabsorbed in the proximal (70%) and distal (10-20%) tubules
◦ Freely filtered form that which is not protein bound
◦ Sodium phosphate cotransporter driven by Na gradient (transporters influenced by acid/base status of filtrate)
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How is phospahte absorption regulated?
* Absorption from intestine - proportional to dietary sodium (cotransport), concentration gradient
◦ Reduced by phosphate binders
◦ Increased by calcitriol (low PO4 also stimulates this) and PTH via calcitriol indirectly
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How is bony redistribution of phosphate regulated
* Bone resorption increased by calcitriol and PTH (PTH both directly and indirectly via increased calcitriol production)
* Renal reabsorption increased by calcitriol (PCT), insulin and thyroxine
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How is renal handling of phosphate regulated?
* Renal reabsorption increased by calcitriol (PCT), insulin and thyroxine?
* Renal elimination increased by
◦ acidosis - Decreased reabsorption in acidosis in the PCT, as more present in H2PO4 which has reduced affinity for transporters. Chronically apical membrane expression reduces
◦ calcitonin
◦ PTH - decreases PTC reabsorption, hypocalcaemia triggers PTH release and renal expression of apical Na/phosphate cotransporters decrease
◦ corticosteroids
◦ hypokalemia
124
What factors increase renal reabsorption of phosphate?
* Renal reabsorption increased by calcitriol (PCT), insulin and thyroxine
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How is reanl excretion of phosphate increased?
* Renal elimination increased by
◦ acidosis - Decreased reabsorption in acidosis in the PCT, as more present in H2PO4 which has reduced affinity for transporters. Chronically apical membrane expression reduces
◦ calcitonin
◦ PTH - decreases PTC reabsorption, hypocalcaemia triggers PTH release and renal expression of apical Na/phosphate cotransporters decrease
◦ corticosteroids
◦ hypokalemia
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What is the physiological role of phosphate?
* Structural role: Bone mineral, phospholipid of cell membrane, DNA and RNA
* Regulatory role: Secondary messenger (IP3); also protein activity is turned on and off by phosphorylation and dephosphorylation
* Metabolic role:
◦ Co-factor in oxygen transport (as 2,3-DPG)
◦ Trapping glucose in cells (as glucose-6-phosphate)
◦ Synthesis of ATP (it's the P in ATP)
◦ Acid-base regulation (urinary and intracellular buffering)
127
High phosphate has what effect?
When phosphate accumulates it contributes to some of the HAGMA of uraemia.
128
At what point does phosphate accumulation occur in renal failure
When the GFR decreases to around 20% of normal, phosphate reabsorption is thought to be maximally suppressed. In this situation, virtually no resorption takes place, and all of the filtered phosphate escapes with the urine.
129
Actions of PTh
PTH
* Increases indirectly PO4 absorption, increased availability of PO4 from bone
* Increases PO4 excretion
* In hyperparathyroidism hypophosphataemia is common
130
Describe the origin, purpose and clearance of sulphate
Sulphate
* Highly charged anion in ECF primarily
* Origin - 10-25mmol pre day
* Prupose
◦ Metabolism of methionine which can be converted into cysteine, homocysteine and tuarine which are sulphur containing amino acids
◦ Essential for protein production
* Clearance - organic cotransporters reabsorption in PCT
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Describe the origin of urate?
* From purine metabolism --> xanthine --> xanthine oxidase to urate
◦ In the liver
◦ No way to metabolise urate --> excreted in gut or urine
* Urate/uric acid is not very water soluble, and crystalises at physiological pH --> gout
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Urate clearance occurs how?
* Urate clearance
◦ 70-90% renal
‣ Filtered freely
‣ 90% Reabsorption with sodium cotransport in PCT where 50% of it is secreted back out
‣ It is also reabsorbed in exchange for excretion of organic anion bases e.g. formate, oxalate, lactate and weakly acidic antibiotics e.g. beta lactam antibiotics (URAT1 transporter) and the site of probenicid
‣ Urate excretion can be ramped up quite a lot so accumulation doesn't occur until end stage
◦ Gut - passive migration where intestinal bacteria feed on it
* Doesnt't cause too much acidosis but can cause renal failure
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What forms does potassium come in for administration
KCl vs Kacetate
KCl – 10ml sterile water, 10ml KCl. 0.75g per ampoule. 2000mosm/kg osmolality. Potassium acetate is the same
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What is the osmolality of KCL
KCl vs Kacetate
KCl – 10ml sterile water, 10ml KCl. 0.75g per ampoule. 2000mosm/kg osmolality. Potassium acetate is the same
135
What is the response to 60mmol of KCL being given
Response to 60mmol of KCl – 60mmol of each. 60ml of water redistributed between all sites. Cl extracellular, K intracellular depending on preinfusion (in K excess more K from infusion remains outside cell proportionally 35%, vice versa down to 7%). K uptake intracellularly over minutes. If K spread evenly then 60mmol into 42L (Vd 70-70% of total body mass)
During infusion K leaves extracellular fluid up until it reaches a plateau of rate of ECF exit. Subsequently at infusion end K continues to be lost but more slowly into ICF. Worse by vol. than saline for ^Cl
136
Illustrate the change in potassium that occurs with administration
During infusion K leaves extracellular fluid up until it reaches a plateau of rate of ECF exit. Subsequently at infusion end K continues to be lost but more slowly into ICF.
137
How quickly does K move post infusion intracellualrly?
minutes
138
What does the rise in K extracellualrly depend on aftger administration?
K intracellular depending on preinfusion (in K excess more K from infusion remains outside cell proportionally 35%, vice versa down to 7%). K uptake intracellularly over minutes. If K spread evenly then 60mmol into 42L (Vd 70-70% of total body mass)
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How does the body handle chronically elevated K
More Na/K ATPases in muscle elading to K sink
140
What is the concentration and mass of bicarbonate in 100mmol bottle
8.4% (84g) per litre, and 100mmol per 100ml bottle of Na and HCO3. pH 7.8. 2 particles therefore 2000 msom/ kg.
141
What is the pH of bicarbonate solution
8.4% (84g) per litre, and 100mmol per 100ml bottle of Na and HCO3. pH 7.8. 2 particles therefore 2000 msom/ kg.
142
What is the osmolality of bicarbonate?
8.4% (84g) per litre, and 100mmol per 100ml bottle of Na and HCO3. pH 7.8. 2 particles therefore 2000 msom/ kg.
143
What happens if you give 100mmol of bicarbonate
SO what happens when you give 100mmol of it: Some bicarbonate excreted by the kidney, 50% metabolised to CO2 and water and disappears from fluid shift calculations. Na in extracellular fluid. Vd of bicarbonate changes according to weight, if it I a low pH much is used as a buffer and change in concentration is small (large apparent Vd), however if alkalotic most remains in body fluids (Vd can be small 0.4L/kg)
Giving sodium bicarbonate consumes free hydrogen ions subsequently leading buffer resevoirs of H+ to settle back towards baseline and release more hydrogen ions until the system rests at a slightly higher pH. CO2 rise.
Bicarbonate levels will come to rest ~26 regardless of whether renally excreted or consumed in H+ reaction.
The act of giving 100ml of hypertonic fluid (Na load) results in ECF fluid distribution – 100ml remains IV + 235ml mobilised from intracellular 83ml gain IV, 251ml interstitial. Na rise 140 143. Serum osmolalioty increases by 2.4mosm/L <1%, and volume expansion 1.6%. Oncotic pressure fall PCT drop in reabsorption
If 100mmol given to pH 7.4, HCO3 24 very rapidly 60% lost due to rapid buffering dropping HCO3 to 26 redistribution then occurs over minutes dilution HCO3 in extracellular water. Reanl excretion then removes the remaining.
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What happens to 100mmol of NaHCO3 when given to someone with normal pH?
If 100mmol given to pH 7.4, HCO3 24 very rapidly 60% lost due to rapid buffering dropping HCO3 to 26 redistribution then occurs over minutes dilution HCO3 in extracellular water. Reanl excretion then removes the remaining.
145
Side effects of exogenous bicarbonate administration
SE: HyperNa, HypoCa, volume overload, cardiovascular depression, ?Intracellular acidosis due to CO2 rise, hypoK
146
Describe the effect of 100mmol of bicarbonate on fluid balance
The act of giving 100ml of hypertonic fluid (Na load) results in ECF fluid distribution – 100ml remains IV + 235ml mobilised from intracellular 83ml gain IV, 251ml interstitial. Na rise 140 143. Serum osmolalioty increases by 2.4mosm/L <1%, and volume expansion 1.6%. Oncotic pressure fall PCT drop in reabsorption
147
What is the fate of the bicarbondate after infusion exogenously?
SO what happens when you give 100mmol of it: Some bicarbonate excreted by the kidney, 50% metabolised to CO2 and water and disappears from fluid shift calculations. Na in extracellular fluid. Vd of bicarbonate changes according to weight, if it I a low pH much is used as a buffer and change in concentration is small (large apparent Vd), however if alkalotic most remains in body fluids (Vd can be small 0.4L/kg)
148
What chemically is in phosphate replacement
KH2PO4 – 1mmol K, 2mmol hydrogen ions, 1mmol phosphate therefore 10mmol = 10mmol K, 20mmol H+, 10mmol PO4, 1.36g per 10mls. Or if Na phosphate 1.56g
149
What i the pH and osmolality of phosphate replacement
KH2PO4 – 1mmol K, 2mmol hydrogen ions, 1mmol phosphate therefore 10mmol = 10mmol K, 20mmol H+, 10mmol PO4, 1.36g per 10mls. Or if Na phosphate 1.56g
PH 4.5
Osmolaity 2000mosm/kg
150
What happens if you give exogenous phosphate? 20mmol
Monovalent phosphoric acid dominant (pKa 7.5, and for divalent 6.2)
If you give 20mmol of KH2PO4 – 20mls. Minimal effect from volume. Rapid equilibration of ions between compartments, PO4 sucked into cells by Na/PO4 cotransporters (insulin promotes), K behaviour as above.
Expect 10mmol PO4 to increase it by 0.45mmol/L i.e. ~65% of phosphate remains extracellular as ECF 15L. So to increase PO4 concentration by 0.45 requires increasing ECF PO4 by 0.65mmol or thereabouts.
151
How much should you expect phosphate 10mmol to increase ECF phosphate by?
Monovalent phosphoric acid dominant (pKa 7.5, and for divalent 6.2)
If you give 20mmol of KH2PO4 – 20mls. Minimal effect from volume. Rapid equilibration of ions between compartments, PO4 sucked into cells by Na/PO4 cotransporters (insulin promotes), K behaviour as above.
Expect 10mmol PO4 to increase it by 0.45mmol/L i.e. ~65% of phosphate remains extracellular as ECF 15L. So to increase PO4 concentration by 0.45 requires increasing ECF PO4 by 0.65mmol or thereabouts.
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