MTT4 Physiology Flashcards
two major applications of diuretic agents
1) reduce circulating blood volume
2) removal of excess body fluid (oedema)
Loop diuretics mechanism of action
inhibit NKCC2 (a Na+/K+/Cl- transporter) in thick ascending limb of LOH, reducing reabsorption of Na+ K+ and Cl- = rapid diuresis
Loop diuretics clinical uses and unwanted effects
clinical uses: acute pulmonary oedema, chronic heart failure, cirrhosis of liver, resistant hypertension, nephrotic syndrome, AKI
Unwanted effects: dehyrdation, hypokalaemia, metabolic alkolosis (Due to H+ loss in urine), deafness
How do loop diuretics cause hypokalaemia
They cause increased Na+ delivery to distal tubule, this is exchanged for K+ which is excreted ub urine
Thiazide diuretics mechanism of action
act in distal tubule to inhibit apical Na+Cl- cotransporter. Causes Na+ excretion and water follows
Thiazide clinical uses and unwanted effects
clinical uses: hypertension, oedema, mild heart failure
unwanted effects:
hypokalaemia (due to urinary K+ loss), metabolic alkolosis (due to urinary H+ loss), increased plasma uric acid - gout, hyperglycaemia, increased plasma cholesterol, male impotence
symptoms of mild and severe hypokalaemia
mild: fatigue, drowsiness, dizziness, muscle weakness
severe: abnormal heart rhythm, muscle paralysis, death
two subcategories of K+ sparing diuretics
aldosterone antagonits and non-aldosterone antagonists
K+ sparing diuretics: spironolactone mech of action
spironolactone metabolised to canrenone (active metabolite), a competitive antagonist of aldosterone receptor. Reduces Na+ channel formation and its absorption from DT. As mech of action depends on reduction of protein expression in DT cells, it takes several days to tak effect
spironolactone clinical uses and unwanted effects
clinical uses: heart failure and oedema
unawnted effects: hyperkalaemia, metabolic acidosis (due to increased plasma H+), GI upset, gynaecomastia, menstrual disorders, testicular atrophy.
Eplerenone produces less unwanted effects than spironolactone
K+ sparing non-aldosterone antagonists triamterene and amiloride mech of action
Clinical use and unwanted effects
act on DT to inhibit Na+ reabsorption and decrease K+ excretion. Blocks luminal Na+ channel by which aldosterone produces its main effects
clinical use: little use alone but used together other diuretics
unwanted effects: hyperkalaemia, metabolic acidosis, GI disturbances, skin rashes
Why do we use diuretics in combination
1) to increase diuretic effect:
a) some pts do not respond well to just one
b) comb of diuretics with diff sites of action can sometimes provide synergistic action
2)to avoid unwanted effects of hypokalaemia
eg loop diuretics witH K+ sparing diuretics or diuretics containing K+
Carbonic anhydrase inhibitor example, mech of action, clinical use, unwanted effects
azetozolamide
mech action: blocks sodium bicarbonate reabsorption in PT
clinical use: glaucoma (reduces intraocular pressure), epilepsy (Reduces vol and pressure of CSF)
unwanted effects: metabolic acidosis (due to excretion of HCO3-), enhances renal stone formation (due to alkaline urine)
how does water act as a diuretic
increased fluid intake leads to reduced ADH secretion from post pituatary due to reduction in plasma osmality. Reduced expression of AQP2 channels on apical surface of DT and collecting duct means more water excretion
Lithium and demeclocycline are drugs which inhibit ADH at collecting tubule. What are unwanted effects
1) can cause diabetes insipidus
2) renal failure reported for both drugs
3) Li+ can cause tremors, mental confusion, cardiotoxicity, thyroid dysfunction and leukocytosis
4) demeclocycline shouldn’t be used in patients with liver disease
agents which inhibit ADH release and and agents which increase its release thus reducing urine excretion
inhibit: alcohol
increase: nicotine, ether, morphine, barbiturates
xanthines examples, what are there effects. why are they rarely used clinically
caffeine, theophylline
produce diuretic effect by increasing CO, and vasodilation of glomerular afferent arteriole
results in inc renal and glomerular blood flow which inc glomerular filtrationand urine output
rarely used due to gastric irritant effects
Osmotic diuretic example, mech of action, clinical uses and unwanted effects
mannitol
non reabsorbable solute which undergoes glomerular filtration
clinical uses: treat cerebral oedema, glaucoma, orally can cause osmotic diarrhoea, acute renal failure
unwanted effects: presence in blood exerts osmotic pressure leading to inc plasma volume, so can’t be used in pts with hypertension
Which thiazide diuretic is most useful for mild heart failure, and which is preferred for hypertension
heart failure: bendroflumethiazide
HT: indapamide
at what pH levels does death occur
<6.8, >8.0
How can you gain H+
> CO2 in blood (combines with H2O to form carbonic acid)
> Non-volatile acids from metabolism (e.g. lactic acid)
> Loss of HCO3- in diarrhoea
> Loss of HCO3- in urine
treatment of respiratory acidosis and metabolic acidosis
metabolic: >give IV isotonic HCO3-
>Give IV lactate solution (Converted to HCO3- buffer in liver)
respiratory: >restore ventilation
>treat underlying disease
>give IV lactate solution
how can you suffer a loss of H+
> Use of H+ in metabolism of organic anions
Loss of H+ in vomit
Loss of H+ in urine
Hyperventilation (blows off CO2
treatment of metabolic and respiratory alkalosis
metabolic: >give electrolytes to replace those lost
>give IV Cl- containing solution
>treat underlying disorder
respiratory: >treat underlying cause
>breathe into paper bag (inc pCO2)
>Give IV containing Cl- containing solution (inc HCO3- excretion)
What about a ureter helps prevent backflow of urine
ureteral openings at oblique angle with slit-like openings
two stages of micturition
it is an autonomic reflex which is inhibited by what and facilitated by what
1) bladder progressively fills until pressure within bladder reaches threshold level
2) this elicits ‘micturition reflex’ which promotes conscious desire to urinate or eventual emptying of bladder
inhibited by higher centres by stimulating continual tonic contraction of external sphincter
facilitated by cortical centres which relax external sphincter
which 3 nerves control micturition and what are there vertebral origin
L2: hypogastric nerve (sympathetic involuntary control)
S2/3: Pevlic nerve (involuntary parasymp control) Pudendal nerve (somatic voluntary control of external sphincter)
The guarding reflex promotes continence. How does this work
progressive bladder distension stimulates pelvic nerve via activation of stretch receptors in bladder wall/ int sphincter. Activation of pelvic nerve leads to activation of hypogastric nerve
hypogastric nerve stimulation causes:
i) relaxation & reduced excitability of bladder detrusor muscle
ii) contstriction of int sphincter
also, ext sphincter held closed by pudendal nerve
how does the micturition reflex coordinate process of micturition
stretch receptors in bladder continue to stimulate pelvic nerve, this causes:
i) contraction of detrusor muscle
ii) relaxation of int sphincter
periodic reflex mictruition contractions also stimulated above 200mL, these relax spontaneously after a few secs.
mictruition contractions cont to be stimulated and relax but >300mL bladder contractions predominate
full bladder sensation conveyed to thalamus and then cerebral cortex. desire to urinate inc
then at approp time, voluntaring relaxation of ext sphincter
3 neural disruptions of micturition
paraplegia (complete severing of nerve inputs from cereb cortex): automatic bladder
partial spinal cord damage with loss of inhibitory descending signals: uninhibited bladder
crush injury to dorsal roots: atonic bladder
3 problems with micturition reflex
1) control can be lost due to alzheimers, stroke, brain tumour
2) bladder sphincter muscle tone lost eg after pregnancy leading to urinary incontinence
3) urinary retentino may develop in males with enlarged prostate glands
3 main types of urinary incontinence
1) loss of sensory nerves - due to injury
2) involuntary bladder contractions - due to injury
3) heightened urge continence - sensitive bladder:
spicy food, caffeine/choc, citrus fruits, carbonated beverages
How does pelvic nerve promote micturation
release ACh, leads to detrusor muscle contraction and int sphincter relaxation
example of an anticholinergic drug and a tricyclic antidepressent and how they are used in urinary incontinence
what are their mechanisms and unwanted effects
antichol: OXYBUTININ
inhibits bladder contractions. facilitates involuntary contr of int bladder sphincter
unwanted effects: dry mouth, blurred vision, palpitations
tricyclic: IMIPRAMINE can be used at low doses for ST treatment of nocturnal enuresis in children over 10
anticholinergic and direct muscle relaxant effects on bladder but also inhibits reuptake of noradrenaline and serotonin inc their levels
side effects: behavioural problems on withdrawal
a) duloxetine?
b) drug useful in children nocturnal bed wetting
c) mirabegron?
a) increases serotonin and NA levels for mod to severe urinary incontinence
b) DESMOPRESSIN
c) selective beta-3 agonist - useful for overactive bladder syndrome
How does hypgastric nerve promote retention
sympathetic nerve that releases NA reduces micturation
2 types of drugs used in urinary retention
alpha-adrenergic blockers
parasympathomimetics (choline esters)
alpha-adrenergic blockers
a) mech of action
b) example
c) cautions
d) unwanted effects
a) antagonist action at alpha-1A adrenoreceptors in bladder neck. relaxes smooth muscle at bladder neck inc urine flow rate
b) Doxazosin
c) can dec blood pressure so careful in pts receiving antihypertensive treatments. avoid in pts with postural hypotension
d) hypotension, drowsiness, depression, headache
parasympathomimetics
a) mech of action
b) example
c) cautions
d) unwanted effects
a) agonist action of ACh receptors, inc bladder contraction via detrusor muscle (usually catheter is preferred over these drugs)
b) BETHANECOL
c) cautions: avoid in pts with cardiac disorders eg arryhtmias
avoid in GI ulceration, asthma, hypotension, epilepsy, pregnancy
d) unwanted effects: nausea, vomiting, intestinal colic, bradycardia, blurred vision
How does ADH work
What two factors effect its release
acts on basolateral V2 receptors of principal cells in collecting duct, leading to insertion of AQP-2 aquaporin channels in apical membrane
plasma osmolality and effective circulating volume (ECV)
for plasma osmolality and ECV:
a) receptors
b) efferent pathways
c) effector
plasma osmolality:
a) osmoreceptors in hypothalamus
b) efferent pathways: ADH and thirst
c) effector: kidney and brain (drinking behaviour)
ECV: a) baroreceptors in carotid sinus, aortic arch, renal afferent arteriole and atria of heart) b) ADH, RAAS, ANP, SNS c) short term: heart, blood vessels long term: kidney
How does decreased ECV stimulate renin release
dec renal perfusion pressure detected by renal baroreceptor.
dec Na+ conc detected by renal Na+ sensor in macula densa cells in DT.
Dec systemic BP also triggers effects of SNS supplying JGA
how does ang II increase ECV
1) Enhances tubular Na+ transport in kidney, promoting Na+ and water resabsorption from tubule
2) stimulation of aldosterone release from adrenal cortex so more Na+ and water is reabsorbed from DT and CD (secreting K+)
3) Acts on hypothalamus to stimulate thirst and ADH release into circulation - water adds to ECV, ADH inc reabsorption of water at CD
4) Vasoconstriction of renal and other systemic blood vessels inc systemic BP
5) Long term ang II causes renal cell hypertrophy so more protein synth of Na+ tranpsorters and channels occur
How does ANS help restore ECV
dec ECV detected by peripheral baroreceptors, signals to hypothalamus in brain, activating ANS which directly effects haemodynamics/activates RAAS, leading to dec Na+ excretion by kidney and inc renal Na+ reabsorption= inc ECV
How does ANP work to LOWER ECV
Inc ECV causes atrial stretch leading to ANP release into circulation. ANP promotes nariuresis. Also causes renal vasodilation so inc blood flow = inc GFR = inc Na+ excreted
More Na+ reaches macula densa so renin release by JGA is reduced - reducing effects of ang II
Net filtration pressure equation
Glomerular capillary pressure - (Bowmans space pressure + glomerular capillary oncotic pressure)
Filtrate has to pass through (in sequence):
pores in glomerular capillary endothelium> basement membrane of bowmans capsule> epithelial cells of bowmans capsule (podocytes) via filtration slits in capsular space
2 hypotheses for autoregulation of blood flow
1) myogenic: autoregulation due to response of renal arterioles stretch (starlings law) eg if BP low, vasoconstriction maintains blood flow
2) metabolic: renal metabolites (Eg NO, adenosine) regulate renal arterioles contraction/ dilation
Series of events that occurs to alter systemic BP via RAS system
A drop in filtration pressure (Eg due to decreased BP) causes dec GFR > dec GFR means less Na+ enters PCT > Macula densa senses a change in DCT Na+ levels > stimulates juxtaglomerular cells to release renin into blood > renin leads to generation of ang II > ang II is a vasoconstrictor causing inc BP > inc BP causes filtration pressure & GFR to return to normal
a) driving force for reabsorption in PCT is what?
b) what follows Na+ in PCT
c) 4 aquaporin channels and where they’re found
d) what else is reabsorbed at PT
a) Na+/K+ATPase pumps 3Na+ in and 2K+ out.
b) Cl- follows by facilitated diff. PO42- and SO42- also cotransported with Na+. H2O follows by osmosis. Glucose cotransported with Na+ too.
c) AQP-1 in PCT
AQP-2 apical surface of collecting duct
AQP-3 &4 basolateral surface of CD
d) 70% of K+, 40-50% urea, amino acids and proteins
How is glucose cotransported efficiently in PT
SGLT2 apical cotransporters in S1 cells of PCT has low affinity for glucose but high capacity. 90% glucose reabsorbed here, glucose crosses GLUT2 on basolateral side
SGLT1 cotransporters on apical side of S3 cells in PST has high affinity but low capacity for glucose, 10% reabsorbed here. Glucose then transported through GLUT1 on basolateral membrane
What are SGLT2 inhibitors used for and why
type II diabetes due to their hypoglycaemic effect
a) 2 types of pumps used to transport compounds from plasma into PT and 2 examples
b) What is significance of PAH ie what is it used for
a) 1. for organic acids eg uric acid, diuretics, penicillin, PAH
2. for organic bases eg creatinine, atropine, morphine
examples: OAT and MRP
b) PAH given as measure of tubular secretion. it is transported from blood into PT cell with alpha-ketoglutarate. It is transported from PT cell into lumen in exchange for an anion in the lumen
1) during formation of urine, what does the LOH
a) descending limb extract
b) ascending limb extract
2) in terms of iso, hyper and hypo tonic, what is state of fluid entering LOH, at tip of LOH and in ascending limb of LOH
1a) extraction of water via AQP-1 channels also some passive movement paracellularly
b) extraction of Na+ K+ and 2Cl- at NKCC2 cotransporter
2) fluid entering LOH is isotonic, fluid at tip of LOH is hypertonic as water has moved out by osmosis, leaving conc urine behind. Fluid in ascending is hypotonic once solutes have been pumped out
Briefly describe countercurrent multiplication in LOH
Active transport of Na+/K+/Cl- into medulla interstitial fluid creates osmotic gradient for water to be reabsorbed out of descending LOH
Urea can diffuse out of CD down conc grad and contribute to hypertonic medulla interstitial fluid
What things are reabsorbed/ secreted in DT. Mention how it is involved in acid-base balance
> Na+ and Cl- reabsorbed in exchange for K+ which is secreted into DT throughout entire DT.
Late DT/ early CD Na+ is exchanged for K+. This involves principal cells, sensitive to aldosterone, and forms a part of RAAS
Na+ exchanged for H+ in DT/ early CD involves alpha and beta intercalated cells
alpha intercalated cells: secrete H+ via H+/Na+ or H+/K+ exchange involving ATPase or H+ATPase. Reabsorbs HCO3-
beta intercalated cells: secrete HCO3- via pendrin cells. reabsorbs H+
lack of ADH leads to diabetes insipidus. What are the two types and treatments
1) nephrogenic: inability for kidney to respond to ADH
treatment: chlortalidone, indometacin
2)neurogenic: due to lack of ADH production by brain.
Treatment: desmopressin, vasopressin, carbamezapine
What is SIADH and what could cause it
Treatment?
Agents which increase ADH release and agent which inhibits
Syndrome of Inappropriate ADH
causes: head injury, drug side effects eg ecstasy
SIADH can cause hyponatraemia and fluid overload
treatment: ADH inhibitors
Increase ADH: nicotine, ether, morphine, barbiturates
Decrease: alcohol
2 reasons we measure renal function
1) identify renal impairment in patients
2) modify drug dosages of drugs cleared by kidneys
what factors put pts at risk of renal failure
> polypharmacy
neonates/ elderly
pts receiving long term analgesia eg NSAIDs
pts receiving nephrotoxic drugs eg ABX
Specific disease (recurrent UTIs, rheumatoid arth, diabetes, hypertension, chronic heart failure, renal disease)
transplant patients
pts undergoing imaging procedures
3 stages to monitoring renal function
1a) clinical assessment (see table notability)
1b) use of bedside clinical data (weight charts, degree of oedema, fluid balance charts, results of urine dip)
2) modern imaging techniques
3) biochemical data eg measure creatinine
what is plasma creatinine a) inc by b) dec by
a) increased by:> large muscle mass/ dietary intake
>drugs which interfere with analysis eg cephalosporins
>drugs which inhibit tubular secretion eg aspirin
>ketoacidosis
>ethnicity (higher in blacks)
b)dec by: > reduced muscle mass eg elederly >cachexia/starvation >immobility >pregnancy >severe liver disease
what is plasma urea measured as?
what is it a) inc by
b) dec by
BUN (Blood urea nitrogen)
a)inc by: >high protein diet
>hypercatabolic conds eg severe burns, severe infection, hyperthyroidism
>GI bleeding (digested blood is source of urea)
>muscle injury
>drugs eg glucocorticoids
>hypovolaemia
b) dec by: >malnutrition
>liver disease
>sickle cell anaemia (due to inc GFR)
>SIADH
Why is inulin theoretically a better measure of renal clearance than creatinine
what are drawbacks of using inulin to measure renal clearnance
How do we measure creatinine clearance accurately
inulin is purely filtered, whereas creatinine is filtered AND secreted into tubule
Has to be administered IV, clinically we use creatinine as it is endogenous
2 methods, one is an overestimation of 20% (see notability), the other an underestimation of 20% (Jaffe method)
Equation for measuring renal clearnace of a molecule
Clearance of X =
Conc of X in urine x Vol of urine formed in given time
_____________________
Conc of X in plasma
Equation for corrected creatinine clearance
ways we can measure creatinine without urine sample (names of equations only)
Creatinine clearance x 1.73
divided by body surface area
cockcroft-gault formula
MORD formula
what substance do we use to measure renal blood flow and why
PAH
it is almost entirely secreted (90%)
Biomarkers of early stages of renal failure
KIM-1
IL-18
FABPs
Cystatin C
2 types of nephron
70-80% cortical nephron (short LOH into medulla)
20-30% juxtamedullary nephron (closer to medulla and long LOH deep into renal pyramid)
order of blood flow in kidney
renal artery> segmental arteries > interlobar arts > arcuate arts > interlobular arts > afferent arterioles > glomerular caps > efferent arteriole > peritubular caps > venules > interlobular veins > arcuate veins > interlobar veins > renal vein
Knob
Dick
