Pharmacology Flashcards
(105 cards)
1
Q
How do diuretics increase urine flow?
A
Inhibit electrolyte reabsorption:
- Mainly Na+ in nephron
- > So reduced water reabsorption
2
Q
What causes oedema?
A
Imbalance between:
- Rate of ISF formation
AND
- Rate of ISF absorption
3
Q
What is ISF formation proportional to?
A
(Pc - Pi) - (πp - πi)
Where:
- Pc is capillary hydrostatic pressure
- Pi is ISF hydrostatic pressure
- πp is capillary oncotic pressure
- πi is ISF oncotic pressure
4
Q
What is the main constituent of πp?
A
Plasma proteins (Mainly albumin)
5
Q
How does Nephrotic syndrome cause oedema?
A
Reduces πp
6
Q
How does CHF cause oedema?
A
Increases Pc
7
Q
How does hepatic cirrhosis cause ascites (intraperitoneal oedema)?
A
Reduced hepatic blood flow
-> Increased portal system pressure
-> Increased Pc -> Ascites
Reduced albumin production -> Decreased πp
8
Q
How does increased ISF formation lead to further oedema?
A
- Blood volume and cardiac output reduced
- RAAS Activation (as there is renal hypoperfusion)
- Sodium and water retention
- Increased blood volume
- Increased Pc and further decreased πp
9
Q
What sort of oedema does CHF cause?
A
Pulmonary (+/- peripheral)
10
Q
What drugs block Na+ reabsorption in the PCT?
A
Carbonic anhydrase inhibitors
11
Q
What drugs block Na+ reabsorption in the Loop of Henle?
A
Loop diuretics
12
Q
What drugs block Na+ reabsorption in the DCT?
A
Thiazide diuretics
13
Q
What drugs block Na+ reabsorption in the collecting duct?
A
Potassium-sparing diuretics
14
Q
Where do most diuretics act, the apical membrane or the basolateral membrane?
A
Apical
15
Q
What drugs are transported into the filtrate by Organic Anion Transporters (OATs)?
A
Acidic drugs:
- Thiazides - Loop diuretics
16
Q
What drugs are transported into the filtrate by Organic Cation Transporters (OATs)?
A
Basic drugs:
- Triamterene - Amiloride
17
Q
In regards to OATs, how do organic anions enter the cell at the basolateral membrane?
A
Diffusion
Exchange for α-ketoglutarate
18
Q
How is the [α-ketoglutarate]i kept high?
A
Transported into cell via a Na+-dicarboxylate transporter:
- Na+ from Na+/K ATPase
19
Q
How do organic anions enter the lumen at the apical membrane?
A
Via the Multidrug Resistant Protein 2 (MRP2)
And via OAT4 (in exchange for α-ketoglutarate)
20
Q
Why do thiazides predispose to gout?
A
Uric acid competes with thiazides at MRP2:
- Increases [Uric acid]p -> Gout
21
Q
How do organic cations move across the basolateral membrane?
A
Diffusion (if uncharged)
OR
Organic Cation Transporters
22
Q
How do organic cations enter the lumen at the apical membrane?
A
Via MRP1
OR
Organic Cation+/H+ antiporters (OCTN)
23
Q
What transporter do Loop diuretics block in the thick ascending loop of the Loop of Henle? How do they do this?
A
The Na+/K+/Cl- co-transporter:
24
Q
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
A
- Diuretic binds to Cl- site on NKCC2 in TAL of Henle
- Reduced tonicity of medullary ISF
- Filtrate is less dilute in thick ascending limb of Loop of Henle
- Increased Na+ load in DCT and CD
- Potassium loss
- Increased calcium and magnesium excretion
25
What percentage of filtered Na+ is excreted on the use of IV loop diuretics?
15-25%
26
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?
-> Hyperpolarisation
-> Reduced Calcium influx -> Relaxation
27
Loop diuretics are strongly bound to plasma proteins, how does this affect their transport into the nephron lumen?
They rely heavily on OATs
28
True or false; Loop diuretics are poorly absorbed from the GI tract?
False
29
Which of the following is not a major use of loop diuretics:
- Acute pulmonary oedema (IV)
- CHF
- Chronic kidney failure
- Ankle oedema
- Hepatic cirrhosis with ascites
- Nephrotic syndrome
Ankle oedema
30
Why do loop diuretics have a reduced effect in nephrotic syndrome?
There is protein in the tubules so the diuretics bind to them
31
Which of the following is not an adverse effect of loop diuretics:
- Hypokalaemia
- Impaired glucose tolerance
- Metabolic alkalosis
- Hypovolaemia and Hypotension
- Hypocalcaemia and Hypomagnesaemia
- Hyperuricaemia
Impaired glucose tolerance
32
How can hypokalaemia be prevented when diuretics are used?
K+ supplement
OR
Add a K+-sparing diuretic
33
What drugs have increased toxicity when a patient is hypokalaemic?
Digoxin
Class III antidysrhythmic drugs:
- Amiodarone and Sotalol
34
How can diuretics cause metabolic alkalosis?
H+ secretion is increased in the collecting ducts
35
What do thiazide diuretics block?
Na+/Cl- co-transporter in the early DCT
36
What are the two best examples of thiazide diuretics?
Bendroflumethiazide
| Hydrochlorothiazide
37
What are the two best examples of thiazide-like diuretics?
Metolazone
| Indapamide
38
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
39
What percentage of filtered Na+ do thiazides cause to be excreted?
~5%
40
How do thiazide diuretics enter the PCT?
Via OATs
41
Which of the following is not a use for thiazide diuretics:
- Hypertension
- Mild CHF
- Nephrolithiasis
- Chronic hepatitis
- Nephrogenic Diabetes Insipidus
- Severe pulmonary oedema
Chronic hepatitis
42
True or false; Thiazide diuretics can cause erectile dysfunction?
True
43
True of false; Thiazide diuretics do not affect glucose tolerance?
Fale - They impair it
44
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
45
How does ADH work in the collecting ducts?
Acts via GPCRs to increase the number of aquaporins to allow more water reabsorption
46
What channels excrete K+ into the lumen at the apical membrane?
Renal outer medullary K+ channels (ROMK)
47
What causes the lumen to become more negative?
Increased Na+ reabsorption:
- Depolarizes basolateral vs apical membrane
- > As Cl- reabsorption
48
As the lumen becomes more negative, how is this corrected?
Increased K+ driving force:
- Increased K+ secretion to balance charge
- > H+ secretion also increased
49
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
50
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
51
What is spironolactone metabolised to that has the most diuretice action?
Canrenone
52
How do spironolactone and eplerenone gain access to the cells of the DCT and collecting duct?
Via basolateral membrane:
| - They are lipophilic
53
What is the GI absorption like for Triamterene and Amiloride?
Triamterene -> Good
| Amiloride -> Poor
54
When are aldostereone antagonists indicated?
CHF
Conn's
Resistant hypertension
Secondary hyperaldosteronism (in hepatic cirrhosis)
55
What type of diuretic is Mannitol?
An osmotic diuretic
56
What is the structure of Mannitol?
A membrane impermeant polyhydric alcohol
57
True or false, osmotic diuretics are pharmacologically inert?
True
58
How does Mannitol enter the nephron?
By glomerular filtration
59
Are osmotic diuretics reabsorbed?
No
60
How do osmotic diuretics work?
Increase filtrate osmolarity which results in the opposition of water reabsorption
61
Where is the primary site of action of Mannitol and why is this the primary site?
PCT:
| - Most iso-osmotic water reabsorption
62
What is a secondary effect of Mannitol?
Reduces Na+ reabsorption in PCT
63
What type of renal failure can mannitol prevent?
Acute hypovolaemic renal failure
64
Apart from renal failure, when else is mannitol used? How does it help these states?
Increased ICP
Increased IOP
Increased plasma osmolality extracts water from these components
65
What type of drug is Acetazolomide?
Carbonic Anhydrase inhibitor
66
What does Acetazolomide do?
Increases the excretion of:
- Bicarbonate
- Na+
- K+
- Water
67
What does Acetazolomide result in due to the effect it has on urine excretion?
Alkaline diuresis:
- Relieve dysuria
Metabolic acidosis
68
How does Acetazolomide work in the treatment of glaucoma and post-ocular surgery?
Reduces IOP by reducing aqueous humour production
69
What ekse can Acetazolomide be used to treat?
Altitude sickness prophylaxis
| Infantile epilepsy
70
What causes Neurogenic DI?
Lack of ADH secretion from posterior pituitary
71
How is Neurogenic DI treated?
Desmopressin:
- V₂-Selective GPCR
- > Avoids increased BP associated with V₁
72
What causes Nephrogenic DI?
Nephrons become insensitive to ADH:
- Usually due to recessive/X-linked mutations
- > In V₂ receptor
73
How is Nephrogenic DI treated?
It can't be
74
What drugs inhibit ADH?
Lithium
Demeclocycline
'Vaptans'
75
How do 'Vaptans' work?
Competitive antagonists of ADH receptors (V₁ₐ, V₁ᵇ and V₂)
76
What does activation of V₁ₐ receptors cause?
Vasoconstriction
77
What does activation of V₂ receptors cause?
Water reabsorption
78
Where does the activation of V₂ receptors have its affects and how?
In collecting duct:
| Aquaporin-containg vesicles directed to apical membrane
79
What happens if V₂ receptors are blocked?
Increased water excretion
| No Na+ accompanies the water so increased [Na+]p
80
What are some examples of 'Vaptans' and what receptors do they block?
Conivaptan (V₁ₐ and V₂)
| Tolvaptan (V₂)
81
When might 'Vaptans' be used?
CHF
| Most value in Hypervolaemic Hyponatraemia by reducing preload
82
What channels is glucose absorbed through in the PCT?
SGLT1 + 2
83
When is glycosuria present?
If [Glucose]filtrate >11mmol/L
84
Where is SGLT1 expressed?
Intestines and kidneys
85
Where is SGLT2 expressed?
Almost exclusively in the nephron PCT
86
Describe the process and features of glucose reabsorption by SGLT2?
S1 segment
90% of reabsorption
Low affinity
High capacity
87
Describe the process and features of glucose reabsorption by SGLT1?
S2/3 segment
10% of reabsorption
High affinity
Low capacity
88
How is glucose reabsorbed at the apical membrane?
Secondary active transport
89
How is glucose reabsorbed at the basolateral membrane?
Facilitated diffusion
90
What is the stoichiometry of each SGLT receptor?
SGLT1 -> 2 Na+ : 1 Glucose
| SGLT2 -> 1 Na+ : 1 Glucose
91
What does SGLT2 inhibition result in?
Glycosuria
92
What are some examples of SGLT2 inhibitors?
Canagliflozin
Dapagliflozin
Empagliflozin
93
What effects do SGLT2 inhibitors have in T2DM?
Glucose excretion
Reduces HbA1c
Reduces weight
94
What are some side effects of SGLT2 inhibitors?
Glycosuria -> Increases bacterial and fungal UTI risk
95
Where is PGE₂ formed?
Renal medulla
96
Where is PGI₂ (Prostacyclin) formed?
Glomeruli
97
What are the functions of prostaglandins?
Vasodilate
| Natriuretic
98
Which of the following does not result in prostaglandin synthesis:
- Ischaemia
- Mechanical trauma
- Angiotensin II
- Hyperkalaemia
- ADH
- Bradykinin
Hyperkalaemia
99
How much of an effect do prostaglandins have on RBF and GFR in normal people?
Very little
100
When do prostaglandins become more important?
In vasoconstriction
| If there is a decrease in effective arterial BP
101
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
102
How do NSAIDs precipitate acute renal failure?
Inhibit COX so decrease prostaglandin synthesis
103
When especially do NSAIDs reduce GFR?
In conditions were renal blood flow depends on prostaglandins:
- Liver cirrhosis
- CHF
- Nephrotic syndrome
104
What drug combination can be bad?
ACEi + Diuretic + NSAIDs
105
What do Probenecid and Sulfinpyrazole do?
Block reabsorption of urate in PCT
