diuretics Flashcards
what kind of action do diuretics exhibit?
diuretic action
what are the two common examples of purines that have a diuretic effect?
Theophylline
2.Caffeine
what kind of a diuretic is caffeine?
mild diuretic that shows CNS stimulation
what kind of a diuretic is theophylline?
more potent diuretic, but less CNS stimulation. Also operates as a muscle relaxant
how do caffeine and theophylline work?
Compounds work by inhibiting phosphodiesterase
what is Aminophylline? and what is it used for?
theophylline+ ethylenediamine. Used as a bronchodilator for treatment of asthma and COPD
what is carbonic anhydrase used for?
regulation of acid/base balance
production of bicarbonate rich aqueous humor secretion (malfunction leading to glaucoma)
secretion of electrolytes in many tissues, e.g. CSF formation
•Saliva production and bile production
how may different isoforms have been identified of carbonic anhydrase?
14 different isoforms have been identified in higher vertebrates
what is carbonic anhydrases function?
- Carbonic anhydrase catalyses a number of chemical reactions.
- Most important physiological reaction is the reaction of water and CO2to form carbonic acid
what is carbonic anhydrase?
Metalloenzyme containing a Zn2+ ion
•The metal sits at the bottom of a 15 Å-cleft and is coordinated by 3 histidine residues
what is the 4th occupied site in carbonic anhydrase?
4th coordination site is occupied by a water molecule/hydroxide ion- active
why is the zinc ion critical in the carbonic anhydrase binding?
The zinc ion sits at the bottom of a cleft which has two distinct faces –a hydrophobic face and a hydrophilic face
•The hydrophobic face is important for binding the substrate and the hydrophilic face is important for shuttling protons in and out
what is carbonic anhydrases role in the kidney?
Bicarbonate is filtered in the glomerulus, but most is reabsorbed
•Bicarbonate reabsorption depends on H+ secretion into the lumen
•H+ are recycled by carbonic anhydrase which is present in the cytoplasm of the cells
what was Acetazolamide used for?
in the treatment of glaucoma but not used as a diuretic anymore.
what is the MOA of Acetazolamide?
Inhibits CAII which reduces the production of aqueous humour leading to a 25-30% reduction in intraocular pressure
what is Inhibits acetazolamide suppressed by?
superseded by other water soluble topical anti-glaucoma agents –dorzolamideand brinzolamide
what affect does acetazolamide inhibiting CA2 have?
- This results in an increase in the secretion of bicarbonate, sodium and potassium ions….
- …..with the concomitant osmotic equivalent of water
- this situation produces metabolic acidosis
what functional group does all carbonic anhydrayse inhibitors have?
All carbonic anhydrase inhibitors have a sulfonamide group
how do carbonic anhydrases inhibitors, acting on CAII bind ?
binding via the ionised sulfonamide moiety
what does a primary sulfonamide mean?- in CAII?
primary sulfonamide means that they will have a certain affinity for one or more isoforms of CA
•May not be the main MOA of these drugs
how do loop diuretics work?
Loop diuretics work by inhibiting the Na+/K+/2Cl-transporter in the lumenal membrane of the thick ascending limb
what are examples of loop diuretics?
Furosemide, bumetamide and torseamide are all examples of loop diuretics•
in thiazide like diuretics, what substitution will make it neutral?
•3,4-tautomer predominates at pH>8.•Substitution of the sulfonamide H will make that moiety neutral…
what does hydrothiazides refer to?
Hydrothiaziderefers to 3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide
•Still have the acidic sulfonamide
what does hydrogenation of the 3,4 double bond in thiazide diuretics do?
Hydrogenation of the 3,4-double bond improves diuretic activity but also reduces CA activity
true or false thiazides are generally more resistant to hydrolysis in acid and alkali hydrrthiazides?
false- opposite
what position is the preferred sulfonamide group on the benzene ring of thiazides and hydro thiazides preferred at?
must have a 10 sulfonamide group (preferably in position 7)
does saturation in positions 3 and 4 makethe thazide more or less active?
more active
what position is a halogen important on in thiazides/ hydro?
position 6
what happens when there is substitution at position 3?
Substitution at the 3 position gives rise to a set of compounds with diverse activity –the cyclopentyl methyl moiety is optimum
what is tolerated in position 2?
small alkyl group
what can the sulphone in position one be replaced by?
can be replaced with a carbonyl group and activity maintained
what are thiazides MOA?
- Thiazides operate in the distal convoluted tubule where they inhibit the Na+/Cl-cotransporter
- they bind to the Cl-binding site of the protein
- The result is the loss of Na+and Cl-, which leads to a contraction in blood volume
- Also increased renin secretion, angiotensin formation, and ultimately aldosterone secretion
what are the 2 aldosterone antagonists?
spironolactone and eplerenone- competitive antagonists - both have a weak diuretic effect
what does aldosterone do?
•Aldersteroneis a hormone produced by the adrenal cortex that promotes Na+reabsorptionin the collecting ducts
what are the 4 structure relation activity for aldosterone antagonists?
- Ketone at C-3 is important for activity
- A relatively planar A/B ring juncture –better if C=C double bond at C4,C5
- Substitution in the B ring is important for oral absorption
- A 5-membered spirolactoneof specific configuration at C17 (R)
what would a clinical investigation of AKI entail?
full family history/ physical examination/ urine and blood examination and radiological studies
what are the 3 pathologies of AKI and what are their clinical findings?
Hypovolaemia-Hypotension /Low cardiac output/Shock
Oliguria-Fluid overload
Hyperkaelmia- Arrhythmias
what is the management for Hypovolaemia?
Plasma, dextran, saline( Inotropes)
what is the management for Oliguria?
Osmotic or loop diuretic (highdose)Fluid / Na restriction Bladder catheter
what is the management Hyperkaelmia?
Mild: Binding in gut with cationic ion exchange resin –polystyrene sulphonate
what is the intracellular and extracellular concentration of potassium?
intracellular concentration of 140 to 150 mEq/L
•The extracellular concentration of 3.5 to 5.0mEq/L
what are the two mechanisms which plasma potassium is regulated by?
–Renal mechanisms that conserve or eliminate potassium
–A transcellular shift between the ICF and ICFcompartments
define hypokalemia
Hypokalemia refers to a decrease in plasmapotassium levels below 3.5 mEq/L
define hyperkalemia
Hyperkalemia refers to an increase in plasma levels of potassium in excess of 5.0 mEq/L
what changes in an ECG in hyperkalemia and hypokalemia?
hyper-low p wave, prolonged PR/ widening of QRS/ peaked T
hypo- PR prolongation/ depressed ST segment/ low T/ prominant U wave.
what are the 3 ways to treat hyperkalemia?
Stabilise cellmembrane potential
shift K+ into cells
remove k+ from body
how do you stablise membrane potential?
I.V calcium gluconate (10ml of 10%solution )
how do you shift k+ into cells?
Inhaled Beta 2 agonists eg. SalbutamolIV
glucose (50ml of 50%solution )
Insulin (5U Actrapid)
Intravenous sodium bicarbonate(100mlof 8.4%)
how do you remove k+ from the body?
IV furosemide and normal saline Ion exchange resin (eg. Resonium)Dialysis
how would you identify and manage acidosis?
Low plasma bicarbonate-Bicarbonate infusion
how would you identify and manage Uraemia?
Nausea, vomiting Diarrhoea Pruritus-Osmotic or loop diuretic (high dose)Fluid / Na restriction Bladder catheter
how would you identify and manage Non-specfic azotaemia?
Tiredness ,lethargy -Adequate non-nitrogenous caloric intake
