Flashcards in Pharmacology Deck (105):
How do diuretics increase urine flow?
Inhibit electrolyte reabsorption:
- Mainly Na+ in nephron
-> So reduced water reabsorption
What causes oedema?
- Rate of ISF formation
- Rate of ISF absorption
What is ISF formation proportional to?
(Pc - Pi) - (πp - πi)
- Pc is capillary hydrostatic pressure
- Pi is ISF hydrostatic pressure
- πp is capillary oncotic pressure
- πi is ISF oncotic pressure
What is the main constituent of πp?
Plasma proteins (Mainly albumin)
How does Nephrotic syndrome cause oedema?
How does CHF cause oedema?
How does hepatic cirrhosis cause ascites (intraperitoneal oedema)?
Reduced hepatic blood flow
-> Increased portal system pressure
-> Increased Pc -> Ascites
Reduced albumin production -> Decreased πp
How does increased ISF formation lead to further oedema?
1. Blood volume and cardiac output reduced
2. RAAS Activation (as there is renal hypoperfusion)
3. Sodium and water retention
4. Increased blood volume
5. Increased Pc and further decreased πp
What sort of oedema does CHF cause?
Pulmonary (+/- peripheral)
What drugs block Na+ reabsorption in the PCT?
Carbonic anhydrase inhibitors
What drugs block Na+ reabsorption in the Loop of Henle?
What drugs block Na+ reabsorption in the DCT?
What drugs block Na+ reabsorption in the collecting duct?
Where do most diuretics act, the apical membrane or the basolateral membrane?
What drugs are transported into the filtrate by Organic Anion Transporters (OATs)?
- Loop diuretics
What drugs are transported into the filtrate by Organic Cation Transporters (OATs)?
In regards to OATs, how do organic anions enter the cell at the basolateral membrane?
Exchange for α-ketoglutarate
How is the [α-ketoglutarate]i kept high?
Transported into cell via a Na+-dicarboxylate transporter:
- Na+ from Na+/K ATPase
How do organic anions enter the lumen at the apical membrane?
Via the Multidrug Resistant Protein 2 (MRP2)
And via OAT4 (in exchange for α-ketoglutarate)
Why do thiazides predispose to gout?
Uric acid competes with thiazides at MRP2:
- Increases [Uric acid]p -> Gout
How do organic cations move across the basolateral membrane?
Diffusion (if uncharged)
Organic Cation Transporters
How do organic cations enter the lumen at the apical membrane?
Organic Cation+/H+ antiporters (OCTN)
What transporter do Loop diuretics block in the thick ascending loop of the Loop of Henle? How do they do this?
The Na+/K+/Cl- co-transporter:
Put the following steps of the pharmacophysiology of how loop diuretics work:
- Filtrate is less dilute in thick ascending limb of Loop of Henle
- Increased calcium and magnesium excretion
- Reduced tonicity of medullary ISF
- Diuretic binds to Cl- site on NKCC2
- Increased Na+ load in DCT and CD
- Potassium loss
1. Diuretic binds to Cl- site on NKCC2 in TAL of Henle
2. Reduced tonicity of medullary ISF
3. Filtrate is less dilute in thick ascending limb of Loop of Henle
4. Increased Na+ load in DCT and CD
5. Potassium loss
6. Increased calcium and magnesium excretion
What percentage of filtered Na+ is excreted on the use of IV loop diuretics?
Loop diuretics have an indirect vasodilator action which makes them useful in pulmonary oedema. What are the possible mechanisms by how this works?
Increase levels of vasodilating prostaglandins?
Reduce response to Angiotensin II and NA?
Open K+ channels in resistance vessels?
-> Reduced Calcium influx -> Relaxation
Loop diuretics are strongly bound to plasma proteins, how does this affect their transport into the nephron lumen?
They rely heavily on OATs
True or false; Loop diuretics are poorly absorbed from the GI tract?
Which of the following is not a major use of loop diuretics:
- Acute pulmonary oedema (IV)
- Chronic kidney failure
- Ankle oedema
- Hepatic cirrhosis with ascites
- Nephrotic syndrome
Why do loop diuretics have a reduced effect in nephrotic syndrome?
There is protein in the tubules so the diuretics bind to them
Which of the following is not an adverse effect of loop diuretics:
- Impaired glucose tolerance
- Metabolic alkalosis
- Hypovolaemia and Hypotension
- Hypocalcaemia and Hypomagnesaemia
Impaired glucose tolerance
How can hypokalaemia be prevented when diuretics are used?
Add a K+-sparing diuretic
What drugs have increased toxicity when a patient is hypokalaemic?
Class III antidysrhythmic drugs:
- Amiodarone and Sotalol
How can diuretics cause metabolic alkalosis?
H+ secretion is increased in the collecting ducts
What do thiazide diuretics block?
Na+/Cl- co-transporter in the early DCT
What are the two best examples of thiazide diuretics?
What are the two best examples of thiazide-like diuretics?
Put the following steps of the pharmacophysiology of how thiazide diuretics work:
- Prevent dilution in early DCT
- Increased Na+ load in late DCT
- Increased calcium reabsorption
- Inhibit Na+/Cl- carrier by binding to Cl- site
- Potassium loss
1. Inhibit Na+/Cl- carrier by binding to Cl- site
2. Prevent dilution in early DCT
3. Increased Na+ load in late DCT
4. Potassium loss
5. Increased calcium reabsorption
What percentage of filtered Na+ do thiazides cause to be excreted?
How do thiazide diuretics enter the PCT?
Which of the following is not a use for thiazide diuretics:
- Mild CHF
- Chronic hepatitis
- Nephrogenic Diabetes Insipidus
- Severe pulmonary oedema
True or false; Thiazide diuretics can cause erectile dysfunction?
True of false; Thiazide diuretics do not affect glucose tolerance?
Fale - They impair it
What does aldosterone do in the late DCT and collecting duct?
Increases the synthesis of Na+/K+ ATPase via increased gene transcription
Increases the synthesis of a protein that activates Epithelial Na+ Channel on the apical membrane:
- Makes them open more frequently
These result in Na+ and water retention and K+ excretion
How does ADH work in the collecting ducts?
Acts via GPCRs to increase the number of aquaporins to allow more water reabsorption
What channels excrete K+ into the lumen at the apical membrane?
Renal outer medullary K+ channels (ROMK)
What causes the lumen to become more negative?
Increased Na+ reabsorption:
- Depolarizes basolateral vs apical membrane
-> As Cl- reabsorption
As the lumen becomes more negative, how is this corrected?
Increased K+ driving force:
-Increased K+ secretion to balance charge
-> H+ secretion also increased
How do Amiloride and Triamterene work?
Block apical ENaC:
- Reduces Na+ reabsorption
- Lumen is less negative
- Reduced K+ secretion
-> As charge doesn't need balanced
How do Spironolactone and Eplerenone work?
Compete with intracellular aldosterone receptors:
- Reduces ENaC activating protein synthesis
- Reduces Na+/K+ ATPase synthesis
-> Both cause reduced K+ excretion
What is spironolactone metabolised to that has the most diuretice action?
How do spironolactone and eplerenone gain access to the cells of the DCT and collecting duct?
Via basolateral membrane:
- They are lipophilic
What is the GI absorption like for Triamterene and Amiloride?
Triamterene -> Good
Amiloride -> Poor
When are aldostereone antagonists indicated?
Secondary hyperaldosteronism (in hepatic cirrhosis)
What type of diuretic is Mannitol?
An osmotic diuretic
What is the structure of Mannitol?
A membrane impermeant polyhydric alcohol
True or false, osmotic diuretics are pharmacologically inert?
How does Mannitol enter the nephron?
By glomerular filtration
Are osmotic diuretics reabsorbed?
How do osmotic diuretics work?
Increase filtrate osmolarity which results in the opposition of water reabsorption
Where is the primary site of action of Mannitol and why is this the primary site?
- Most iso-osmotic water reabsorption
What is a secondary effect of Mannitol?
Reduces Na+ reabsorption in PCT
What type of renal failure can mannitol prevent?
Acute hypovolaemic renal failure
Apart from renal failure, when else is mannitol used? How does it help these states?
Increased plasma osmolality extracts water from these components
What type of drug is Acetazolomide?
Carbonic Anhydrase inhibitor
What does Acetazolomide do?
Increases the excretion of:
What does Acetazolomide result in due to the effect it has on urine excretion?
- Relieve dysuria
How does Acetazolomide work in the treatment of glaucoma and post-ocular surgery?
Reduces IOP by reducing aqueous humour production
What ekse can Acetazolomide be used to treat?
Altitude sickness prophylaxis
What causes Neurogenic DI?
Lack of ADH secretion from posterior pituitary
How is Neurogenic DI treated?
- V₂-Selective GPCR
-> Avoids increased BP associated with V₁
What causes Nephrogenic DI?
Nephrons become insensitive to ADH:
- Usually due to recessive/X-linked mutations
-> In V₂ receptor
How is Nephrogenic DI treated?
It can't be
What drugs inhibit ADH?
How do 'Vaptans' work?
Competitive antagonists of ADH receptors (V₁ₐ, V₁ᵇ and V₂)
What does activation of V₁ₐ receptors cause?
What does activation of V₂ receptors cause?
Where does the activation of V₂ receptors have its affects and how?
In collecting duct:
Aquaporin-containg vesicles directed to apical membrane
What happens if V₂ receptors are blocked?
Increased water excretion
No Na+ accompanies the water so increased [Na+]p
What are some examples of 'Vaptans' and what receptors do they block?
Conivaptan (V₁ₐ and V₂)
When might 'Vaptans' be used?
Most value in Hypervolaemic Hyponatraemia by reducing preload
What channels is glucose absorbed through in the PCT?
SGLT1 + 2
When is glycosuria present?
If [Glucose]filtrate >11mmol/L
Where is SGLT1 expressed?
Intestines and kidneys
Where is SGLT2 expressed?
Almost exclusively in the nephron PCT
Describe the process and features of glucose reabsorption by SGLT2?
90% of reabsorption
Describe the process and features of glucose reabsorption by SGLT1?
10% of reabsorption
How is glucose reabsorbed at the apical membrane?
Secondary active transport
How is glucose reabsorbed at the basolateral membrane?
What is the stoichiometry of each SGLT receptor?
SGLT1 -> 2 Na+ : 1 Glucose
SGLT2 -> 1 Na+ : 1 Glucose
What does SGLT2 inhibition result in?
What are some examples of SGLT2 inhibitors?
What effects do SGLT2 inhibitors have in T2DM?
What are some side effects of SGLT2 inhibitors?
Glycosuria -> Increases bacterial and fungal UTI risk
Where is PGE₂ formed?
Where is PGI₂ (Prostacyclin) formed?
What are the functions of prostaglandins?
Which of the following does not result in prostaglandin synthesis:
- Mechanical trauma
- Angiotensin II
How much of an effect do prostaglandins have on RBF and GFR in normal people?
When do prostaglandins become more important?
If there is a decrease in effective arterial BP
How do prostaglandins affect GFR?
1. Direct vasodilator effect on afferent arteriole
2. Increase renin release -> Increased Ang II levels -> Efferent arteriole vasoconstricts -> Increased filtration pressure
3. Both increase GFR
How do NSAIDs precipitate acute renal failure?
Inhibit COX so decrease prostaglandin synthesis
When especially do NSAIDs reduce GFR?
In conditions were renal blood flow depends on prostaglandins:
- Liver cirrhosis
- Nephrotic syndrome
What drug combination can be bad?
ACEi + Diuretic + NSAIDs