Quiz 14 Flashcards
1
Q
K sparing Diuretics
Mineralcorticoid Receptor Antagonists
A
- Aldosterone, a steroid hormone, is secreted by the adrenal cortex, and is a potent mineral corticoid.
- Acting on the distal tubule and collecting ducts of the nephron, it causes increased reabsorption of Na+ and Cl– ions and water, while increasing K+-ion ion excretion
- Aldosterone action leads to increase in water retention, and increased blood pressure / volume.
- The biologic effect of Aldosterone is caused by its binding to the mineralcorticoid receptor (MR), a nuclear transcription factor
- Inhibition (antagonism) of aldosterone function can lead to diuresis (excretion of Na+, and Cl– ions and water)
- Such inhibitors are also classified as Potassium-Sparing Diuretics
2
Q
Renin?
Type of enzyme?
A
Protease
Angiotensinogen to form Angiotensin I
3
Q
RAS drug target?
A
4
Q
Osmotic Diuretics?
A
- Low molecular weight compounds
- Passively filtered through Bowman’s capsule into renal tubule.
- Limited reabsorption.
- Undergoes negligible metabolism
- Forms hypertonic solution, causing water to secrete into renal tubule, producing a diuretic effect
5
Q
The action of ACE results in?
A
- Generation of a potent hypertensive agent Angiotensin II
- Release of a hypertensive agent Aldosterone
- Degradation of a potent antihypertensive agent Bradykinin (a vasodilator)
- The outcome of all the above actions of ACE is hypertension, an increase in blood pressure.
6
Q
Losartan
A
- The first clinically approved ARB drug (1995)
- Highly protein bound (~98%); Adequate oral bioavailability (33%)
- Approximately 14% of an oral dose is oxidized by the isozymes CYP2C9 and CYP3A4 to a more potent (10-40 times) carboxylic acid metabolite
- (-CH2OH —-> -CO2H)
- Primarily excreted by the fecal route.
7
Q
Diuretic Sites of Action
A
Proximal Tubule; Loop of Henle; Collecting Tubule
8
Q
Carbonic Anhydrase Inhibitors?
A
- Presence of an acidic sulfonamide group (pKa= 7–9). Free N–H required for activity.
- Site of Action: Proximal Convoluted Tubule
- Not very efficacious (increases renal excretion of sodium only by 2%–5%)
- Limited use, mostly for the treatment of glaucoma (oral and topical formulations)
- First orally effective CA inhibitor diuretic in clinical use § Diuretic effect lasts for 8 – 12 hrs § Limited use because of systemic acidosis
- AEs-
- Development of metabolic acidosis on prolonged use
- Can cause electrolyte disturbance (hypokalemia) and renal effects (kidney stone)
- Hypersensitivity reactions possible (attributable to sulfonamide group)
9
Q
Carbonic Anyhydrase?
A
- Carbonic anhydrase (CA), a metalloenzyme (Zn2+-ion at active site), catalyzes the formation of carbonic acid (H2CO3) from carbon dioxide and water.
- At least seven CA isozymes in human, present mainly in blood cells, gastric mucosa, pancreatic cells, and renal tubules.
- In the proximal tubule, promotes reabsorption of Na+ and HCO3 – ions from the glomerular filtrate, and excretion of H+ ions. (Acidic nature of urine and alkalinity of blood)
- Inhibition of carbonic anhydrase induces diuresis via excretion of sodium and bicarbonate ions, and associated water molecules.
- Accidental initial discovery of carbonic anhydrase inhibitory activity (in dog urine!) of Sulfanilamide, a sulfonamide antibacterial.
10
Q
ACE
Contains?
Cleaves peptides with? But not?
Hydrolyzes Ang I and also?
A
- Zn2+
- Tripeptide sequence but not cleave peptides with penultimate prolyl residue
- Bradykinin and Substance P
11
Q
Ang II receptor blockers application
AEs
DIs
A
- All the ARBs are approved for the treatment of hypertension. Can be used as stand-alone drugs, or in combination with other anti-hypertensive agents (e.g. Diuretics; Calcium channel blockers).
- Additionally, some of the ARBs also find use in the treatment of nephropathy in type 2 diabetes (Losartan / Irbesartan), heart failure (Candesartan / Valsartan), and cardiovascular risk-reduction of MI and stroke (Telmisartan) etc.
AEs
- ARBs are generally well tolerated. Unlike ACE inhibitors, does not effect the levels of bradykinin or prostaglandins. The most common side-effects include:
- Headache; Dizziness; Fatigue; Hypotension; Upper respiratory tract infection etc. q ARBs are contraindicated during pregnancy.
DIs
- ARBs are relatively free of clinically important drug interactions. Telmisartan is the only agent among this class reported to increase the plasma concentration of Digoxin.
- However, non-steroidal antiinflammatory drugs (NSAIDs) may alter the response to ARBs and other anhtihypertensive agents (including ACE inhibitors and Ca2+-channel blockers) due to the inhibition (COX) of vasodilatory prostaglandins.
*
12
Q
Other examples of ACEs in Dicarboxylate group
A
13
Q
Angiotensin II is a?
What is its precursor?
Angiotensin II is also responsible for?
A
- Potent vasodilator
- Angiotensinogen
- Production of Aldosterone which in turn contributes towards an increase in plasma volume and Bp.
14
Q
Properties of loop di table
A
15
Q
Captopril Metabolic Pathway
A
16
Q
AEs of ACE-Is
A
- Generally well-tolerated drugs. Serious untoward reactions are rare.
- Side effects may include, hypotension, hyperkalemia, dry cough (in 5-20% of patients), dizziness, renal insufficiency, skin rash, neutropenia (rare), and angioedema etc.
- The use of ACE inhibitors during pregnancy (especially during 2nd / 3rd trimester) is contraindicated
- Renal elimination is the primary route of elimination for majority of the ACE inhibitors (except Fosinopril). Therefore, dosage should be reduced in patients with renal impairment.
17
Q
The difference in ACE classes? 3 ways
A
- In their potency
- Whether the activity is due to the drug itself, or the conversion of a prodrug to an active metabolite
- Pharmacokinetics (extent of absorption; effect of food; plasma half-life; tissue distribution; mechanism of elimination etc)
18
Q
SAR of Thiazide Diuretics?
A
- C7-position: Sulfonamide group is required for activity
- C6-position (R1): Electron-withdrawing group (e.g. Cl, CF3 etc) required for activity
- 3–4-position: Saturation of the double bond results in more potent (~ 10-fold) analogs
- C3-position (R2): Lipophilic group improves diuretic potency
- 2-position (R3): N-alkyl substitution increases the duration of diuretic action
19
Q
Angiotensin I is converted to? By?
A
to Ang II by ACE
20
Q
Loop Diuretics?
A
- Diverse structural classes
- The most efficacious among the various diuretic classes
- Peak diuresis produced > other commonly used diuretics (High-Ceiling Diuretics)
- Site of Action: Loop of Henle (thick ascending limb)
- Inhibits the luminal Na+/ K+/ 2Cl- co-transporter
- Characterized by quick onset (~ 30 min) and relatively short duration of action (~ 6 hrs)
21
Q
Enalapril
A
- An ester prodrug. Hydrolyzed by hepatic esterase to the active carboxylic acid form. Dicarboxylate class of ACE inhibitor.
- More potent than Captopril.
- Oral drug; Readily absorbed; Oral bioavailability ~ 60%, not reduced by food. Eliminated unchanged in urine
- Enalaprilat not absorbed orally. Available in IV formulation.
- Used for the therapy of hypertension and heart failure; Only ACE inhibitor approved for pediatric use.
22
Q
Fosinopril
A
- Phosphinate group containing ACE inhibitor.
- A prodrug. Cleavage of the ester moiety by hepatic esterases generates the active drug Fosinoprilat
- Slowly and incompletely (36%) absorbed after oral administration.
- Fosinoprilat and glucuronide conjugate excreted in urine and bile; Clearance not significantly altered by renal impairment.
- Indicated for the treatment of hypertension and heart failure.
23
Q
Candesartan cilexitil
A
- Inactive ester prodrug. Completely hydrolyzed during absorption from the GI tract to form the active drug Candestran; High plasma protein binding (99%); Oral bioavailability = 15%; T1/2 = 9 hrs.
25
Q
Captopril
A
- First ACE inhibitor drug (1981); Contains a sulfhydryl (SH) group
- Oral drug; Rapid absorption; Bioavailability ~ 75%; T1/2 = 2 hrs
- Partially eliminated unchanged in urine (~50%), remainder as disulfide dimer and captopril-cysteine disulfide
- Used for the therapy of hypertension and heart failure
- Food reduces oral bioavailability by 25-30%
- Sulfhydryl group implicated in skin rashes and taste disturbance
27
Q
Spironolactone
A
- A semi-synthetic drug. Prevents aldosterone binding (antagonist) to the MR in the distal convoluted tubule and the collecting system.
- Causes increased amount of Na+ / water excretion, and retention of K+-ion.
- Oral drug (90% availability). Undergoes significant first-pass metabolism to form Canrenone (loses Me–CO–SH), an active metabolite. Excretetion mainly in urine.
- Adverse effects: Can cause hyperkalemia. Use of other K+-sparing diuretics, potassium supplements and food rich in potassium should be avoided. Anti-androgenic effects, hypersensitivity reactions, GI disturbances, and peptic ulcer have also been reported.
28
Q
Torsemide
A
- Sulfonylurea side-chain instead of sulfonamide
- Same site / mechanism of action as furosemide and bumetanide
- Available in oral and parenteral (IV) forms
- Partially metabolized by hepatic cytochrome P450 enzymes. A major metabolic route involves oxidn of the Ar-Me group to carboxylic acid.
- Uses: Treatment of hypertension; Congestive heart failure and cirrhosis associated edema.
- Adverse Effects : Fatigue, dizziness, muscle cramps, nausea and orthostatic hypotension.
31
Q
Thiazide-like Diuretics
Quinazolinone
A
- Contains a quinazolin-4-one structural core (ring-SO2 of thiazides replaced with a CO group)
- Diuretic effects similar to the thiazide class of compounds
- Orally active. Long duration of action (upto 24 hrs)
- Adverse effects similar to the thiazide diuretic class
33
Q
RAS a Bp Elevation picture
A
34
Q
Other ARBs in use
Features of all ARBs
A
- All the ARBs are acidic drugs. The tetrazole ring has a pKa ≃ 6, and the carboxylic acid pKa = 3-4.
- Azilsartan medomoxil and Olmesartan medomoxil are prodrugs that are completely hydrolyzed during absorption from the GI tract to generate the active carboxylic acid metabolites.
35
Q
Comparison Table of K sparing Diuretics
A
36
Q
Amiloride
A
- An aminopyrazine derivative.
- Renal epithelial Na+ channel blocker. Blocks the reabsorption of Na+- ion and secretion of K+-ion in DCT. No effect on aldosterone action.
- Oral drug (~50% absorption). Excreted (mostly unchanged) in urine and feces. Renal impairment can increase half-life.
- Adverse Effects: Similar to triamterene.
37
Q
Benzapril
A
- A prodrug; Ester hydrolysis produces the active drug.
- Belongs to the dicarboxylate class of ACE inhibitors
- More potent than captopril or enalaprilat
- Oral drug. Indicated for hypertension.
- Readily but incompletely absorbed. Glucuronide conjugate excreted via urine and bile.
- Also available in combination with Hydrochlorothoazide (Lotensin HCT®) or Amlodipine (Lotrel®)
40
Q
Osmotic Diuretic Examples
Which one has greater absorption? Longer half life? Duration of action?
A
- Isosorbide greater absorption longer t half
- Mannitol greater DOA
- Not a frequently used class of diuretics in current practice, except in the prophylaxis of acute renal failure to inhibit water reabsorption and maintain urine flow.
- Mannitol is the agent most commonly used as an osmotic diuretic.
- Administered as an intravenous solution.
- Isosorbide (a bicyclic form of sorbitol!) is primarily used for the treatment of glaucoma.
41
Q
Pharmacokinetics of ARBs
A
42
Q
Ethacrynic
A
- A phenoxyacetic acid derivative. Lacks a sulfonamide group.
- Same site / mechanism of action as the above loop diuretics
- Rapid onset (~ 30 min) and long duration of action (6 – 8 hr)
- Oral and parenteral. Highly plasma protein bound (> 95%)
- Relatively less potent than the other drugs in this category. However, useful in patients who are allergic to the sulfonamides.
- Adverse effects: Greater incidences of ototoxicity and more serious gastrointestinal effects
43
Q
Site of Mechanism of Action of Diuretics Summary
A
45
Q
Thiazide examples
A
- Used in the treatment of edema caused by congestive heart failure as well as in hepatic or renal disease. Also useful in the treatment of hypertension (reduction in blood volume)
- Compared to Chlorothiazide, the double bond reduced analog Hydrochlorothiazide (HCT) is more potent and has a longer half-life.
- Adverse Effects: Gastric irritation, hypersensitivity, nausea, and electrolyte disturbance. Long-term use may also result in decreased glucose tolerance and increased blood lipid content (TC, LDL, TG).
46
Q
Overview of Site of Mechanism of Action Picture
A
47
Q
SAR of ACE Is
A
- The N-ring carboxylic acid is essential (mimics the C-terminal carboxylate of ACE substrates)
- Large hydrophobic functionalities in the N-ring increases potency
- Zn-ion binding groups (sulfhydryl, carboxylate, phosphinic acid etc) required for potency
- ‘X’ is usually methyl (mimics the side-chain of alanine), the exception being Lisinopril
- For optimum activity, stereochemistry should be consistent with natural L-amino acid
48
Q
Triametrene
A
- Contains a pteridine sturctural core.
- Renal epithelial Na+ channel blocker. Blocks the reabsorption of Na+ ion and prevents excretion of K+ ion in the distal tubule (but no effect on aldosterone action).
- Oral drug (~70% absorption). Metabolized extensively (4’-OH analog and its sulfate conjugate). Excreted in the urine
- Adverse Effects: Can cause hyperkalemia, nausea, vomiting and headache. Potassium supplements are contraindicated, and serum potassium levels should be monitored.
49
Q
Captopril Binding site interaction?
A
51
Q
Comparison of Triametrene and Amiloride
A
52
Q
Furosemide
A
- Contains a carboxylic acid functional group (pKa ~4)
- 8 – 10 Times stronger saluretic action than the thiazides.
- Causes excretion of Na+, K+, Ca2+, Mg2+, Cl- and HCO3 - ions
- Orally active. Parenteral form for faster onset of action.
- Extensive plasma protein binding (> 90%). Mostly excreted unchanged (kidney).
- Uses-Most important use in the treatment of pulmonary edema. Additional uses include, treatment of edemas associated with cardiac, hepatic and renal malfunctions. Also useful in the treatment of hypertension.
- Side-Effects: Electrolyte Imbalance; Hyperuricemia; Gastrointestinal side-effects, and hypersensitivity etc. Can also cause ototoxicity (temporary hearing loss). This effect can be additive with concurrent usage of aminoglycoside antibiotics.
53
Q
Eplerenone
A
- An aldosterone antagonist. Compared to Spironolactone, lower affinity for MR, however a more selective inhibitor (does not inhibit AR, PR, and GR)
- Oral drug (~70% availability). T1/2≃ 5 hr. Hepatic metabolism (CYP3A4). Metabolites inactive and excreted in urine and feces.
- Adverse effects: Can cause hyperkalemia. However, unlike spironolactone, limited/fewer sexual side effects.
55
Q
Pharmacokinetic Properties of ACEs table
A
57
Q
Renin
Only drug in class
A
- Development of Aliskiren: The First (and only) Renin Inhibitor in Clinical Use
59
Q
Bumetanide
A
- Ring substitution pattern different than furosemide
- Greater bioavailability than furosemide
- Marked increase in diuretic potency (~ 40 times of furosemide)
- Uses and side effect profile similar to furosemide
