Heart failure therapeutics Flashcards
What are Loop diuretics ?
- Mechanism of Action ,
Act on Kidneys - loop of henule - target thick ascending limb.
0 Increase production of Urine ————– eliminating water from body.
0 lining of ascending limb -
o contains NA+ , K+ , 2CL- co transporter on apical surface - absorb these ions from thick ascending limb into blood.
HOW IT WORK ?
- Enter bloodstream ——-> Kidney ——————–> peritubular capillaries ( supplied by efferent arteriole (vessel leaving glomerulus ) —————> PCT ————————-> Thick ascending limb.
- Drug binds to CL side on NA / K / 2CL - co -transporter on apical membrane & block it.
- N/K/ CL not reabsorbed from AL lumen into cell - excreted into urine.
- More , NA + in lumen , more H20 in lumen ————> more urine produced.
( because when NA pumped out of lumen into interstitium (medulla ) - medulla is salty - water leaves the descending limb , so filtrate becomes increasingly concentrated ) - also attracts H20 to leave collecting duct - less urine produced , more conc. )
EXAMPLES
- Furosemide
- Bumetanide
- Toreasemide
SIDE EFFECTS
0 Hypokalemic Metabolic Alkalosis
- low serum K + , blood PH increase - too little H+ or too much HCO3-
1. Increased NA in collecting duct - NA moves from lumen of CD to cells lining the CD.( makes lumen more negative )
- This attracts H+ , K+ ions in the cells lining CD - so move into lumen & excreted in urine.
- less K + - hypokalemia
- less H + - more HCO3 in respect - so Metabollic alkalosis .
- also causes increased secretion of MG , CA - hypomagnesia , hypocalcaemia
0 Ototoxic effect - Hearing loss - ear - has NA/K+/2 CL - co transporter as well - effect these transporters in the ear at high conc.
decrease endolymph conc - damage tiny hair cells in inner ear.
0 Allergic reaction to Sulfonamide loop duiretics can cause: - Acute interstitual nephritis - damage kidney ( ethacrynic acid - safer choice )
How does transport of ions in the ascending limb work ?
Function - reabsorption of NA (primary site ) - but impermeable to water ( water retained in tubules )
HOW IT WORKS
- Lumen of ascending limb - high conc of NA + compared to inside cells lining the AL.
- APICAL SURFACE -Transporter moves NA + down conc gradient. One K + , 2 CL- co-transported into cells lining AL.
- BASOLATERAL SURFACE - NA /K + ATPase pump - pumps 3NA + out of cell into interstitum , 2 K + into cell using energy ( helps to maintain low NA conc inside cell so apical transporter keeps moving na , k , cl into cell )
- CL - , K + move out of cell back into lumen of AL by apical channels - leak them passively
- Electrochemical gradient created by passive movement of K+ , cl - - enables Mg 2+ , CA 2+ to sneak into cell —————-> interstitum ————-> blood btw 2 cells.
(paracellular pathway - does not use channels )
Indications of Loop diuertics ?
Contraindications ?
Hypertension - water loss through urine —————–> reduced plasma volume ———————–> reduced cardiac output ———————–> Lower BP
0 Edematous state - Pulmonary oedema , Ascites - fluid build up in extracellular space
( be careful not to remove too much fluid from the body )
oedema - can be caused by heart failure
0 Electrolyte imbalance - correct Hypercalcemia , kalemia ( high CA , K conc in blood )
Without NA/K/CL co transporter CA/K not able to get into blood from lumen of AL (no reabsorption )
- same idea for bromide , fluoride , iodide intoxication ( stop reabsorption of Br, I ,Fu in AL lu )
CONTRAINDICATIONS
- Dehydrated patient
- Hypovolemic patients - should be corrected before treatment
( low circulating volume of fluid triggers PCT to reabsorb more uric acid ) - using loop - diuretic here results in more fluid loss & more reabsorbtion of uric acid - causes :
o Hyperuricemia
o Gout attacks - - hypotension - should be corrected.
- renal failure due to nephrotoxic , hepatoxic drugs.
( cause high conc of Loop diuretics )
Anuria - failure of kidneys to produce urine. - if onset sudden suggest bilateral obstruction to kidneys. - severe hypokalaemia , hyponatraemia
- comatose , precomatose linked to liver cirrhosis
look for enlarged prostate - urinary retention can occur.
be careful :
elderly - dont use as first line for hypertension -safer options
- dont use for ankle oedema with no evidence of heart , liver , renal failure , nephrotic syndrome.
- dont - hypertension + urinary incontience - - make urinary incontinence worse.
Internal ( cell ) K + balance /control
Link btw Hyper / Hypolaemia & acidosis / alkalosis.
Acidosis —- expect to see Hyperkalaemia
0 Cell
- intracellular ( high K + , low H + )
- extracellular ( high H + , low K + )
0 When blood acidotic - TOO high H + conc - H + wants to enter cell -to slow Build up. Moves in
0 But K+ has to move out - to prevent too much positive charge in cell (charge control )
0 As a result , blood becomes Hyperkalaemia.
Alkalosis - expect to see Hypokalaemia
0 potassium remains in cell no H + to drive it out . h + is rather being moved out down conc gradient ( low conc in blood - so moves from cell — blood (opposite of normal )
0 H + moving out ———–> cell more negative ———-> potassium reabsorbed & retained in cell ——> hypokalaemia.
Action of DCT - Nephron - in terms of potassium sparing diuretics
Function
Cells involved .
Lining - contains
- tubal / epithelial cells
- principal cells
0 has :
APICAL MEMBRANE
o ATP -dependent K + pump -
pumps k + out of cell
o NA + channel (ENac ) - pulls
sodium into cell
- alpha - intercalated cells
0 has :
APICAL MEMBRANE
o H - ATPase - pumps H + into DCT
tubule from cell using energy
o H + - K + ATPase - 1 H+ pumped
into DCT tubule , 1 K + pumped into
cell using energy - BASOLATERAL MEMBRANE OF PRINICIPAL & ALPHA CELLS HAVE :
o NA + - K+ ATPase - 3 NA + out of
cell into intersitium , 2 K + into cell .
Expression of pumps regulated by Aldosterone :
IN PRINCIPAL CELL
1. Aldesterone - binds to mineralcorticosteriod receptor in cytoplasm of principal call .
2. Complex of receptor and Aldo enter nuclues.
3. Causes increased expression of ENaC , ATP dependent K + pump & NA ,K + ATPase.
RESULT - NA + reabsorption in blood , increased K + into DCT tubule thus urine.
IN ALPHA INTERCLATED CELL
Aldosterone :
1. Aldesterone - binds to mineralcorticosteriod receptor in cytoplasm of call .
2. Complex of receptor and Aldo enter nuclues.
1. increase expression of H-P ATPase - more H + into DCT tubule , more K+ into cell
Result - Increased H + secretion
What are potassium sparing diuretics ?
Only class of diuretic which retains potassium.
Act on Kidney - DCT & CD
2 types
0 directly- inhibit aldosterone (mineralocorticoid receptor )
o Spirolactone
o Epleronone
( less expression of channels )
0 - indirectly inhibit aldosterone effects -
block ENaC Channels
o Amilloride
o Triamteterene
(blocked ENaC ——> less NA in principal cell ——> decreased action of NA /K + ATPase on basolateral membrane.
Both - increase secretion of NA —————-> water follows —————- > increased H20 loss in urine.
Decrease secretion of H / K +.
(potassium sparing )
Indications of Potassium sparing diuretics ?
Hypertension - water loss through urine —————–> reduced plasma volume ———————–> reduced cardiac output ———————–> Lower BP
0 Edematous state - Pulmonary oedema , Ascites - fluid build up in extracellular space
( be careful not to remove too much fluid from the body )
oedema - can be caused by heart failure
0 They are weak - so used in conjunction with other diuretics e.g loop or thiazide (addition increases reabsorption of K + & prevent hypokalaemia )
0 Type that inhibit aldosterone receptor - used in Hypoaldosteronism - Spiralactone.
(Conn’s syndrome - too much secretion by adrenal gland , or adrenal tumour or secondary - activation of RAAS - low plasma V ———–> fluid into extracellular compartment ——> oedema )
0 Aldosterone receptor antagonist - given after MI - reduce mortality - reduce rate of remodelling of heart.
SPIRALACTONE - Polycystic Ovarian Syndrome - block affects of testosterone ( binds to androgen receptor -)
AMILORIDE - Block ENaC
Liddle’s syndrome ( ENaC channels constantly activated - causes NA retention , K loss )
Side effects of Potassium sparing diuretics
E.g usage with indomethacin
Spiractolone
Triameterene
Etc.
0 Hyperkalaemia
0 Hyperkalaemia ———–> arrhythmias
( close monitoring needed if on potassium supplements or other medication that increases potassium - ACE , ARBs)
0 H + retention - metabollic acidosis
0 SPIRALACTOLONE - antiadrenergic side effects - blocks Testosterone —————–> development of breast tissue in men , impotence - erectile dysfunction
0 Triamterene - kidney stones formation
& Acute renal failure when used with Indomethacin (NSAID )
Action of DCT - Nephron - in terms of thiazide & Thiazide like - diuretics
Function
Cells involved .
Epthelial cells :
has :
APICAL MEMBRANE
0 NA / CL - symporter - 1 NA , 1 CL -
transported into cell from DCT lumen
0 CA channel - CA moves into cell from
lumen
BASOLATERAL
0 Na - CA exhanger - exchanges Ca
inside cell for Na in interstitum
( NA moves into cell , CA moves out into
interstitum )
- NA / CL- reabsorbed by NA/CL symporter into cell.
- NA in cell , along with H20 into interstitum ———-> bloodstream
(H20 follows NA ) - Ca channel - moves Ca into cell
- Ca moves out of cell into interstitium , Na moves into cell - NA / CA exchanger
Mechanism of action of Thiazide & Thiazide like Diuretics ?
- Block / Inhibit NA/CL symporter on APICAL membrane
- less NA / CL absorbed into blood - Excreted into urine instead
- Water follows H20 - so more urine produced.
secreted into tubule by the same system that secretes uric acid - competes with uric acid
- so increase level of uric acid in the blood - hyperuricemia ——–> gout attacks
Difference btw Thiazide & Thiazide like diuretics ?
Thiazide - Benzothiadazine derivatives
e.g . chlorothiazide
o hydrochlorothiazide
( end in thiazide)
Thiazide like diuretics -
Sulfonamide derivatives
e,g. Metolazone , indapmide , chlorothalidone.
Inidcation of Thiazide / like diurectics ?
Hypertension - water loss through urine —————–> reduced plasma volume ———————–> reduced cardiac output ———————–> Lower BP
- 1ST LINE
0 Edematous state - Pulmonary oedema , Ascites - fluid build up in extracellular space
( be careful not to remove too much fluid from the body )
oedema - can be caused by heart failure
2ND LINE
LESS POTENT VS LOOP by tlonger lasting
CALCIUM REABSORPTION
1. prevent calcuria - cause calcium rebasorption
prevention of calcuria ——————> prevents calcium nephrolithiasis & calcium oxlate kidney stones
- Slows progression of osteoporosis
Nephrogenic diabetes insipidus
kidneys —-> no response to ADH —–> cant absorb water in DCR & CD——> lots of dilute urine produced .
( pl drink lots of water to replace BV )
Thiazide D - induce mild hypovolemia – PCT absorbs more NA , H20 ——–> less fluid reaches DCT & CD.
Side effects of Thiazide / like diurectics ?
0 Hyperglycemia
0 Increased serum cholesterol
0 Hypercalcemia
0 Hyperuricemia ————-> risk of gout - if chronic
0 hyponatuemia ( increase loss in urine )
0 Hypovolemia – increased urine output
( can trigger ADH secretion ————–> CD rebsorbs water ————-> urine more dilure -> urine NA conc further reduced.
0 Hypokalemic metabollic alkalosis
0 Allergic reaction to sulfonamide - allergic reaction to thiazide/ like D.
What are Beta blocker ?
Class 2 antiarrthymic drugs
mainly affects B1 adrenoreceptor
2 Subtypes
Selective B1
0 atenolol 0 acebutolol 0 betaxolol 0 bisoprolol 0 esmolo 0 metoprolol
Non - selective B blockers
o timolol
o propranolol
( Trick to remembering - all beta B end in olol -
selective - first letter (A-M) -1ST half of alphabet
non - selective - (N- Z) - Second half )
PACEMAKER CELLS
- Betablocker binds to B1 adrenorecptor & blocks
ADREN/ NA from binding
( AD/NA need to bind to activate receptor which ultmately leads to opening of L - type CA2+ channels needed to generate action potential ) - Less L- type CA channels open
- decreases the amount of calcium that enters the cell
- slower pacemaker potential
- decrease rate of SAN firing —-> decreased HR
( also decrease conduction velocity in AVN )
LONGER P-R interval on ECG.
longer time btw onset of atrial depolarisation & ventricular depolarisation.
NON PACEMAKER
Indirectly prevent the opening of L-type calcium channels.———————————————–> decreases the amount of intracellular calcium available to the muscle fibers——————————————-> weakening the force generated during heart contraction.
by reducing the heart rate and contractility, beta blockers reduce cardiac oxygen demand.
Indications of Beta Blocker ?
0 supraventricular tachycardias
o atrial fibrillation
o atrial flutter.
therapy and prophylaxis for arrhythmias :
recent myocardial
infarction.
