Pharmacology Flashcards
List the different types of diuretic
Loop
Thiazide
Osmotic
Carbonic anhydrase inhibitors
How to diuretics work (generally)
They cause the excretion of electrolytes (particularly Na and Cl)
This triggers the excretion of water by osmosis
List diseases that produce oedema
Nephrotic syndrome
Congestive heart failure
Hepatic cirrhosis with ascites
What causes oedema
An imbalance between the rate of formation and absorption of interstitial fluid
How does nephrotic syndrome lead to oedema
In this condition, large proteins are allowed into the filtrate from blood
This causes fluid to also move out of blood - enters interstitium
The lower blood volume and renal perfusion activates the RAAS system
This leads to further water retention
How does congestive heart failure lead to oedema
In HF there is reduced cardiac output and therefore reduced renal perfusion
This activates RAAS which leads to water and Na retention
How does cirrhosis lead to oedema (ascites)
Fibrosis in the liver produces a resistance to blood flow, increased liver pressure and decreased albumin
This causes fluid to be lost to the peritoneal cavity = ascites
RAAS is again activated
How do diuretics mobilize the oedema fluid
Diuretic causes excretion of salt and water – blood in kidney becomes more concentrated which draws water from the interstitial fluid (reduced oedema)
Where in the nephron do carbonic anhydrase inhibitors work
Proximal convoluted tubule and the early distal convoluted tubule
Work on the Na/H exchange
Weak diuretic
Where in the nephron do loop diuretics work
Loop diuretics block the triple transporter in the loop of Henle – very strong action
Where in the nephron do thiazide diuretics work
Early distal convoluted tubule
Act on the Na/Cl co-transporter
Where in the nephron do potassium sparing diuretics work
Collecting tubule and duct
Block Na/K exchange
Diuretics usually work at the basolateral membrane of tubular cells - true or false
False
They mostly act on the apical membrane as this is where the transporters are
How do diuretics enter the filtrate
If not bound to large proteins they can enter by glomerular filtration
Organic anion transporters move acidic drugs into the filtrate
Organic cation transporters move basic drugs into the filtrate
Which diuretics are acidic
Thiazide and loop agents
Which diuretics are basic
triamterene and amiloride
How does the organic anion transporter (OAT) work
Na+/K+ works at basolateral membrane
Allows Na to move down the conc gradient – a-KG is co-transported by this
This movement drives OA to enter the cell in exchange for the a-KG leaving the cell again
OA is actively pumped out of apical membrane by a transporter using ATP (primary active transport)
Some OA can be reabsorbed on another antiport system – exchange of OA and a-KG
How does furosemide increase your risk of gout
It reacts with urate in the tubular cells
How does the organic cation transporter work
OC enters the cell against a chemical gradient – driven by electrical gradient
OC is pumped out by primary active transport
Also in the apical membrane the MATE transporter which moves OC out in exchange for H+ ions
How are calcium and magnesium absorbed in the kidney
The negative charge created by the triple transporter drives their movement
They are moved through specific proteins into the interstitium - paracellular route
How does the triple transporter work
2 Cl- move downhill by the triple transporter
Cl leaves the basolateral membrane via a chloride channel
K+ must move uphill – energy comes from Na+ movement
K+ re-enters the tubule and also moves out of the BL membrane via a channel
Movement of 1 Na and K and 2 Cl
How does the triple transporter end up giving the cell negative potential
positive move in and so do 2 negatives. However, the K+ is recycled back into tubule so cell has negative potential
How do loop diuretics work
They block the triple transported in the ascending loop of Henle
This alters the electrolyte balance (less reabsorption) and reduces water reabsorption
Loop diuretics have a venodilator effect - true or false
True
This is useful in treating pulmonary oedema
Loop diuretics have rapid action - true or false
True
Especially with IV administration
Used in emergency treatment of acute pulmonary oedema
What are the clinical indications for loop diuretics
Acute pulmonary oedema Chronic heart failure Chronic kidney failure Hepatic cirrhosis with ascites Nephrotic syndrome Hypertension Increase urine volume in acute kidney failure Reduce acute hypercalcaemia
which loop diuretic is best for those with heart failure
Bumetanide
Furosemide absorption can be unpredictable in CHF
How are loop diuretics processed by the body
Absorbed in the GI tract
Strongly bind to plasma proteins
Enter nephron by the OAT mechanism
When are loop diuretics contraindicated
Severe hypovolaemia or dehydration
Must take caution with severe hypokalaemia or hyponatraemia, hepatic encephalopathy and gout
What are the adverse affects of loop diuretics
Hypokalaemia Metabolic alkalosis - more H+ is secreted Hypocalcaemia and hypomagnesaemia Hypovolaemia and hypotension - elderly Hyperuricaemia - may precipitate gout Dose related loss of hearing
How do thiazide diuretics work
Inhibit the Na/Cl carrier
Prevents dilution of filtrate in the distal tubule
Increases the load of Na in the collecting tubule - causes K loss
Causes more Na excretion = modest diuresis
Thiazide diuretics have a vasoconstrictor effect - true or false
False
It is a vasodilator effect which helps with hypertension treatment
How are thiazide diuretics absorbed
Well absorbed in GI tract
Enter nephron by OAT mechanism
What are the clinical indications for thiazide diuretics
Mild heart failure Hypertension Severe resistant oedema - with a loop Renal stone disease - reduces amount of Ca in filtrate Nephrogenic diabetes insipidus?
List examples of thiazide diuretics
Bendroflumethiazide
Indapamide, metolazone - thiazide like
When are thiazide diuretics contraindicated
Hypokalaemia
Must be cautious in hyponatraemia and gout
What are the adverse effects of thiazide diuretics
Hypokalaemia Metabolic alkalosis Hypovolaemia and Hypotension Hyperuricemia - may precipitate gout Erectile dysfunction Impaired glucose tolerance in diabetics
How can thiazide diuretics be used in osteoporosis
They help reabsorb calcium
How does aldosterone act in the kidney
It acts on cytoplasmic receptors to active the ENaC channel
This allows more Na reabsorption
Aldosterone also increases abundance of Na/K ATPase so you can also pump the excess Na out of the cell as well
How do the potassium sparing diuretics work
Amiloride and Triamterene - block apical sodium channel and decrease its reabsorption
Spironolactone and eplerenone - compete with aldosterone to prevent it activating ENaC
How do loop and thiazide diuretics cause K+ loss
The increase the load of Na in the filtrate
Some is reabsorbed which makes the lumen more negative
These both increase driving force for K+ secretion into filtrate and it is lost in the urine
How are spironolactone and eplerenone absorbed by the body
Well absorbed from GI tract
Spironolactone is rapidly metabolised to canrenone which is the active part
How are amiloride and triamterene absorbed in the body
T is well absorbed in the GI tract, A is not
Enter nephron via OCT in proximal tubule
When are potassium sparing diuretics contraindicated
Severe renal impairment
Hyperkalaemia
Addison’s disease
What are the clinical indications for potassium sparing diuretics
Used alongside other diuretics to counteract potassium loss
Heart failure
Hyperaldosteronism - Conns
Resistant hypertension
secondary hyperaldosteronism (due to hepatic cirrhosis with ascites)
How do osmotic diuretics work
They enter the nephron by glomerular filtration
Increase the osmolarity of the filtrate which opposes the absorption of water
They also decrease sodium reabsorption in the proximal tubule - higher fluid volume so Na conc decreased
Where is the major site of action of osmotic diuretics
Proximal tubule
As this is where most isosmotic reabsorption of water occurs
When are osmotic diuretics used
In prevention of acute hypovolaemic renal failure - maintains urine flow
In urgent treatment of raised intracranial and intraocular pressure
How do osmotic reduce intracranial and intraocular pressure
Solute itself doesn’t get into eye or brain (due to BBB) but increases plasma osmolarity
This creates a osmotic gradient that draws fluid into the blood – reducing pressure
what are the adverse effects of osmotic diuretics
Transient expansion of blood volume
Hyponatraemia
When else might osmotic diuresis occur (without use of diuretics)
In hyperglycaemia - the excess glucose in the urine means the filtrate retains fluid
As a consequence of iodine radiocontrast dyes - dye is excreted and takes some water with it
Give an example of an osmotic diuretic
Mannitol
Give an example of a carbonic anhydrase inhibiter
Acetazolamide
What are carbonic anhydrase inhibitors used for
Not used as diuretics anymore
Reducing intraocular pressure - glaucoma
Prophylaxis of altitude sickness
Some forms of infant epilepsy
How do carbonic anhydrase inhibitors work (in kidney)
Inhibit carbonic anhydrase
This increases excretion of HCO3 with Na, K and H20
Gives an alkaline diuresis
How is alkalising the urine useful
It can relive dysuria
Prevents crystallisation of weak acids - decreases formation of uric acid stones
Enhances secretions of weak acids
How does vasopression (ADH) work
Released from posterior pituitary
Binds to G protein coupled receptor = increased cAMP
This increases insertion of aquaporin 2 channels into the apical membrane
More water is reabsorbed
What causes neurogenic diabetes insipidus
Caused by lack of vasopressin secretion from the posterior pituitary
How do you treat neurogenic diabetes insipidus
Desmopressin
Synthetic analogue of vasopressin but selective for V2 receptor
Doesn’t cause the vasoconstriction
What substances can affect vasopressin secretion
Ethanol inhibits secretion
Nicotine enhances it
What causes nephrogenic diabetes insipidus
Mutations in the V2 gene - usually recessive and X linked
This prevents the nephron from responding to vasopressin
No current treatment
How do aquaretics work
Act as competitive antagonists of vasopressin receptors
This causes excretion of water without accompanying Na
Give examples of aquaretics
Tolvaptan
Conivaptan
How is tolvaptan used
Syndrome of inappropriate ADH secretion
Role in HF being investigated
Where is SGLT2 expressed
In the proximal tubule of the kidney
How do SGLT2 inhibitors work
Block SGLT2 to prevent reabsorption of glucose
Leads to glycosuria - glucose excreted
This decreases HbA1c and leads to weight loss
Used in diabetes treatment
Name some SGLT2 inhibitors
Dapagliflozin
Canagliflozin
SGLT2 inhibitors cause a diuresis - true or false
True
A mild one
What are the functions of prostaglandins that are made in the kidney
Vasodilators
They are produced in response to ischaemia, mechanical trauma, angiotensin II, ADH and bradykinin
How do prostaglandins affect GFR
Only affect GFR if there is widespread vasoconstriction or decreased blood flow
They cause vasodilation of the afferent arteriole and trigger renin release
Why might NSAIDs precipitate renal failure
They inhibit COX which decreases prostaglandins
Can lead to issues if the kidneys need to prostaglandin mediated vasodilation
What is an adverse drug reaction
Any undesirable reaction (whether expected or not) that leads to detriment in the wellbeing of the patient in the absence of another explanation
Give examples of drugs with a low therapeutic index
gentamicin, lithium, digoxin, warfarin, vancomycin, theophylline
Adverse drug reactions are common in which groups
The elderly and frail
Those with multiple morbidities - renal/hepatic impairment
Polypharmacy
Drugs with low therapeutic index
What is a Type A adverse drug reaction
Due to augmented pharmacological effect
Dose dependant and predictable
Give examples of Type A adverse drug reactions
Diuretics can cause pre-renal failure and dehydration if too high a dose is given
ACEi shouldn’t be taken if you have D&V
Drug-drug interaction
Drug-food interaction
Drug disease interaction
What is a Type B adverse drug reaction
Includes bizarre, unpredicted effects of a drug
Not dose dependent
These are the dangerous ones - can be fatal
Give examples of Type B adverse drug reactions
Drug rashes
Bone marrow aplasia
Hepatic necrosis
What is a Type C adverse drug reaction
Chronic effects of the drug
Occurs with prolonged therapy
Need to monitor these drugs and tell patients about them
Give examples of Type C adverse drug reactions
Steroids in Cushing’s - osteoporosis
NSAIDs can lead to hypertension
What are Type D adverse drug reactions
Delayed effects of a drug
May occur years after stopping treatment
Often cardiogenic or teratrogenic
Give examples of Type D adverse drug reaction
Secondary malignancy post-chemo
What are Type E adverse drug reactions
End of treatment effects
Occurs with abrupt withdrawal of a drug as you can get rebound effects
What is a Type F adverse drug reaction
Failure of therapy
