Agents Acting on the Nephron

which drugs act on the proximal tubule

carbonic anhydrase inhibitors

SGLT2 inhibitors

which drugs act on the descending loop

osmotic agents

which drugs act on the ascending loop

loop diuretics

which drugs act on the collecting duct

potassium sparing diuretics

aldosterone antagonists

ADH agonists and antagonists

which drugs act on the distal tubule

thiazide diuretics

describe the mechanism of action of carbonic anhydrase inhibitors

inhibits reabsorption of bicarbonate in the proximal tubule

alkalises the urine

blood becomes more acidic

main use of carbonic anhydrase inhibitors

glaucoma

name the 3 carbonic anhydrase inhibitors

acetazolamide

brinzolamide

dorzolamide

acetazolamide

- formulation

- indication

- oral

- glaucoma, altitude sickness

brinzolamide and dorzolamide

- formulation

- indication

- eye drops

- open angle glaucoma/ ocular hypotension

SGLT2 meaning

sodium glucose co transporter 2

what is another name for SGLT2 inhibitors

gliflozins

name 5 SGLT2 inhibitors

Dapagliflozin, Canagliflozin, Empagliflozin, Ertugliflozin

what do the SGLT2 inhibitors do

selectively and reversible inhibit SGLT2

what does the inhibition of SGLT2 lead to

reduces reabsorption of glucose

reduces sodium reabsorbtion

what does the reduction of glucose and sodium reabsorption result in

urinary excretion of glucose and osmotic diuresis

what does an increase of sodium in the distal tubule lead to

a decrease in intraglomerular pressure

-> leads to reduction of volume overload, reduce BP, lower preload and afterload

all of which are beneficial to the heart

adverse effects of SGLT2 inhibitors

vulvovaginitis

balanitis (inflamed penis)

UTI

constipation, nausea, thirst

fourniers gangrene - pain in genitalia

SGLT2 interactions

thiazide and loop diuretics - dehydration and hypotension

other antihypertensives - hypotension

insulin and insulin secretagogues - hypoglycaemia

osmotic agents (mannitol) - what does it act on

proximal tubule

descending loop of henle

collecting ducts

mannitol MOA

- inhibits passive water reabsorption -> this leads to an increase in tubular fluid volume

- draws water

- secondary decrease in Na+ reabsorption

- Na+ is filtered -> causes osmotic diuresis

How is mannitol administered?

IV

not absorbed orally

clinical uses of mannitol

- decrease intracranial pressure and intraocular pressure

- acute renal failure

osmotic agents adverse effects

transient expansion of extracellular fluid volume

hypotraemia

headache

nausea

vomiting

osmotic agents interactions

- nephrotoxic drugs - kidney damage

- neurotoxic drugs - CNS toxicity

- diuretics - may potentiate effects

name 2 thiazide diuretics

Bendroflumethiazide

Hydrochlorothiazide

name 2 thiazide like diuretics

• Chlortalidone • Indapamide

thiazide (like) diuretics MOA

- block distal renal tubular reabsorption

- bind to the Cl- site on the Na+/Cl- co-transport system

- inhibits action of co-transporter

- causes natriuresis with loss of Na+ and Cl- in the urine

what are the 2 types of potassium sparing diuretics

amiloride

aldosterone antagonists

amiloride site of action

collecting tubules and collecting ducts

amiloride MOA

- block luminal epithelial sodium channels (ENAC)

- decrease Na reabsorption and K excretion

- action is independent of aldosterone

effect of amiloride

limited diuretic efficacy

adds to the natriuretic effect

reduces kaliuretic effect of other diuretics

amiloride use

combined with thiazide/loop diuretics to prevent hypokalaemia

alternative to oral potassium supplements

amiloride adverse effects

hyperkalemia

GI disturbances - nausea, vomiting, diarrhoea

amiloride interactions

ACE

ARB

Potassium salts

NSAID

Digoxin

name 2 aldosterone antagonists

spironolactone

eplerenone

aldosterone antagonists MOA

- compete with aldosterone for intracellular receptor

- decrease Na reabsorbtion and K secretion

- weak diuretic effect

clinical use of potassium sparing diuretics

oedema assoc with HF

severe HF

adjuvant in resistant hypertension

primary/secondary hyperaldosteronism

aldosterone antagonists adverse effects

hyperkalemia

GI upset

gynaecomastia

menstrual disorders

testicular atrophy

aldosterone antagonists interactions

ACE

ARB

other drugs increasing K+

antihypertensives

name an antidiuretic hormone (ADH) agonist

desmopressin

what is desmopressin an analogue of

vasopressin

desmopressin clinical indications

diagnosis and treatment of central diabetes insipidus

symptomatic treatment of nocturia in adults

haemophilia

von Willebrands disease

name an ADH antagonist

tolvaptan

tolvaptan use

vasopressin receptor antagonist

polycyctic kidney disease treatment

hyponatraemia secondary to SIADH

ADH agonist adverse effects

hypotraemia

nausea

ADH antagonist adverse effects

• Dehydration

• Dry mouth

• Gout

• Hyperglycaemia

• Hypernatraemia

• Hyperuricaemia

• Thirst

• Polydipsia

• Acute hepatic failure

ADH agonist - desmopressin interactions

lamotrigine

loperamide

ADH antagonist - tolvaptan interactions

concurrent use of drugs increasing serum sodium and/or potassium conc

name 2 loop diuretics

furosemide

bumetanide

loop diuretics MOA

Inhibit Na⁺/K⁺/2Cl⁻ co-transporter in the thick ascending limb of the Loop of Henle

- this normally absorbs 25% filtered Na

what does the inhibition of the co transporter lead to

• ↑ Na⁺ delivery to distal tubule

• ↓ medullary hypertonicity

• ↓ water reabsorption in collecting duct

physiological effects of loop diuretics

powerful diuresis

natriuresis

increased renal blood flow via prostaglandin sunthesis

loop diuretics adverse effects

hypokalemia

exacerbate diabetes

precipitate gout

dose related hearing loss

why should older adults start with lower dose of loop diuretic

as they are more prone to side effects

loop diuretics interactions

NSAIDS - reduced diuretic effect

antihypertensives

PPIs - hypomagnesaemia

aminoglycosides/vanomycin = hearing loss/ ototoxicity

risperidone

benefits of ACE/ARB to kidneys

protective effects on kidneys

patients with diabetes should use them regardless of their BP

causes vasodilation

reduced sodium retention

decreases vasoconstriction

ACE/ ARB negatives

decrease in angiotensin II means the efferent arteriole doesn't constrict so glomerular pressure drops and GFR falls

what is acute kidney injury

abrupt reduction in kidney function

what does acute kidney injury result in

accumulation of nitrogenous waste products and other toxic substances

why are most cases of acute kidney injury hospital patients

Kidneys are predisposed to haemodynamic injury due to hypovolaemia or hypoperfusion

causes of acute kidney injury

pre renal

renal/ intrinsic

post renal

symptoms of acute kidney injury

oliguria - low urine output

pre renal

hypovolaemia

decreased cardiac output

decreased effective circulating volume - chf/ liver failure

impaired renal autoregulation - nsaids, ace/ arbs, cyclosporin

renal/ intrinsic

glomerular/vascular

sepsis

ischaemia

nephrotoxins

post renal

bladder outlet obstruction

bilateral pelvoureteral obstruction

prostaglandins and renal function

renal prostaglandins are vasodilator and natriuretic

biosynthesis is low under basal conditions

when vasocontrictors are released, local prostaglandins compensate to preserve renal blood flow

where is PGE2 active

renal medulla

where is PGI2 active

the glomeruli

NSAIDS and liver

nsaids have no effect on a healthy liver

however, if they are given to those with poor renal function, NSAIDS can increase blood pressure and salt and water retention and acute renal failure can occur

factors stimulating prostaglandin synthesis in kidneys

ischaemia

angiotensin II

ADH

bradkinin

drugs which cause renal failure if combined

RAAS inhibitor + NSAID + diuretic

acute kidney injury - the triple whammy

RAAS inhibitor - decrease glomerular filtration

NSAID - blockade of COX2 preventing prostacyclin synthesis = increased risk of AKI

Diuretic - can contribute to AKI by causing hypovolaemia

chronic kidney disease

reduction in GFR or urinary abnormalities

incidence increases with age

CKD and AKI are not mutually exclusive

RAAS plays a key role in the progression of CKD

renal effects of angiotensin II

short term increase GFR

long term can worsen CKD and cause glomerular scarring

cause of chronic kidney disease

ischaemic renal disease

metabolic disease (diabetes)

urinary tract diseases

renal stones

hereditary

chronic kidney disease can lead to

polyuria and nocturia

proteinuria and albuminuria

hypertension

anaemia

uraemia

bone disease

neurological changes

treatment/management of CKD

control BP

dietary modification

treat anaemia and nausea

manage vit d deficiency

osmotic diuresis

water is drawn

pulling effect