Loop diuretics

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Loop Diuretics

Overview

Loop diuretics are the most potent class of diuretics available, capable of inducing a brisk natriuresis even when renal function is significantly compromised. They are sometimes called high-ceiling diuretics because their dose-response curve reaches a substantially higher maximum than other diuretic classes. The four agents available are furosemide, bumetanide, torsemide, and ethacrynic acid.

Chemical Classification

Drug	Chemical Class	Sulfonamide Moiety
Furosemide	Sulfonamide-based	Yes
Bumetanide	Sulfonamide-based	Yes
Torsemide	Sulfonylurea	Yes
Ethacrynic acid	Phenoxyacetic acid derivative	No

Ethacrynic acid is the only loop diuretic without a sulfonamide moiety, making it the agent of choice in patients with a confirmed sulfa allergy. Its reactive methylene group forms a covalent adduct with cysteine's free sulfhydryl group, and this cysteine adduct is the active form of the drug.

Chemical structures of furosemide and ethacrynic acid

Furosemide (top) and ethacrynic acid (bottom). The shaded methylene group on ethacrynic acid is reactive and combines with sulfhydryl groups. - Katzung's Basic and Clinical Pharmacology, 16th Ed.

Site and Mechanism of Action

Loop diuretics act primarily in the thick ascending limb (TAL) of the loop of Henle, where they bind to and inhibit the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2/SLC12A1) on the luminal (apical) membrane of tubular epithelial cells.

Why is this site so effective?

The TAL normally reabsorbs ~25% of the filtered Na⁺ load
Nephron segments downstream of the TAL lack the reabsorptive capacity to compensate for the massive salt delivery escaping the TAL
The proximal tubule, by contrast, reabsorbs ~65% of filtered Na⁺, but diuretics acting only there have limited efficacy because the TAL rescues most of the escaped load

Secondary consequences of NKCC2 inhibition:

Reduced lumen-positive transepithelial potential (normally generated by K⁺ recycling back into the lumen) - this potential is the driving force for divalent cation reabsorption, so blocking it increases Mg²⁺ and Ca²⁺ excretion
Disruption of the hypertonic medullary interstitium, impairing water reabsorption in the collecting duct even in the presence of AVP (antidiuretic hormone) - resulting in nearly isotonic urine
Increased Na⁺ and water delivery to the distal nephron markedly enhances K⁺ excretion, especially in the presence of elevated aldosterone levels

Prostaglandin effect: Loop diuretics induce renal COX-2 expression, increasing prostaglandin (particularly PGE₂) synthesis. PGE₂ itself inhibits salt transport in the TAL, contributing to the diuretic response. This explains why NSAIDs (which inhibit COX-2) can blunt the response to loop diuretics.

Goodman & Gilman's The Pharmacological Basis of Therapeutics
Katzung's Basic and Clinical Pharmacology, 16th Ed.
National Kidney Foundation Primer on Kidney Diseases, 8th Ed.

Pharmacokinetics

Drug	Oral Bioavailability	t½	Elimination	Onset (oral)
Furosemide	~60% (variable: 12-112%)	~1.5 h	~65% renal, ~35% hepatic	2-3 hours
Bumetanide	~80%	~0.8 h	~62% renal, ~38% hepatic	Similar to torsemide
Torsemide	~80-90% (consistent)	longer	Predominantly hepatic	~1 hour
Ethacrynic acid	~100%	~1 h	~67% renal, ~33% hepatic	-

Key pharmacokinetic points:

All loop diuretics are highly protein-bound (mainly albumin) and therefore reach the tubular lumen primarily by active tubular secretion via organic anion transporters (OAT1/OAT2) at the basolateral membrane of the proximal tubule - NOT by glomerular filtration
Tubular secretion is impaired by: endogenous organic acids (accumulate in CKD and uremia), NSAIDs, probenecid, and salicylates - all competing for the same transporter
Furosemide has the most variable bioavailability - the coefficient of variation is 25-43%; switching formulations does not standardize response
Torsemide has more consistent absorption and longer duration (4-6 hours vs. 2-3 hours for furosemide), with at least one active metabolite
In CKD: furosemide pharmacokinetics are most significantly altered; bumetanide and torsemide (both hepatically metabolized) are less affected
National Kidney Foundation Primer on Kidney Diseases, 8th Ed.
Katzung's Basic and Clinical Pharmacology, 16th Ed.
Goodman & Gilman's

Relative Potency

Drug	Equivalent Dose
Furosemide	20 mg (or 40 mg by some references)
Torsemide	10 mg
Bumetanide	0.5 mg
Ethacrynic acid	~50 mg

Bumetanide is approximately 40x more potent than furosemide by weight.

Hemodynamic Effects

Beyond diuresis, loop diuretics have direct vascular effects:

Furosemide acts as a venodilator and reduces right atrial and pulmonary capillary wedge pressure within minutes of IV administration - before measurable diuresis occurs
This effect is prostaglandin-mediated and is blocked by indomethacin
Furosemide also increases renal blood flow via prostaglandin-mediated vasodilation of renal vasculature
There may be a transient rise in systemic vascular resistance due to renin secretion stimulation at the macula densa (RAS activation) - this reinforces the importance of combining loop diuretics with vasodilators in acute pulmonary edema with preserved BP
Braunwald's Heart Disease

Clinical Uses

Indication	Notes
Acute pulmonary edema	First-line; rapid venodilation + natriuresis reduces LV filling pressures
Chronic heart failure	Reduces mortality, hospitalizations, worsening HF; torsemide may be preferred over furosemide due to more reliable absorption
Hypertension (resistant or low GFR <30 mL/min)	Loop diuretics preferred; NOT first-line in normal renal function (thiazides are more effective there)
Nephrotic syndrome edema	Often refractory to other diuretics; loop agents may be the only option
Hepatic cirrhosis with ascites	Used with caution to avoid volume contraction
Hypercalcemia	Combined with isotonic saline to prevent volume depletion; increases Ca²⁺ excretion by 30%
Hyperkalemia	Increases urinary K⁺ excretion; combined with IV NaCl if patient is normo-/hypovolemic
Life-threatening hyponatremia	Combined with hypertonic saline; loop diuretics block urine concentration
CKD-related edema	Higher doses needed due to right-shifted dose-response curve
Drug overdose (forced diuresis)	Facilitates renal elimination of offending drug
Acute renal failure	Listed as an indication (to increase urine output)

Goodman & Gilman's; Katzung's

Adverse Effects and Toxicity

Electrolyte and Fluid Disorders:

Hyponatremia - from overzealous use
Hypokalemia - increased distal Na⁺ delivery + aldosterone activation; can precipitate arrhythmias (especially with digoxin)
Hypomagnesemia - K⁺ and Mg²⁺ losses often occur together; a risk factor for arrhythmias
Hypochloremic metabolic alkalosis - increased urinary H⁺ and Cl⁻ loss
Hypocalcemia (rare) - can cause tetany in severe cases; loop diuretics should be avoided in postmenopausal osteopenic women
Volume depletion - hypotension, reduced GFR, circulatory collapse, thromboembolic events
Hepatic encephalopathy - in patients with liver disease, volume depletion can precipitate this

Ototoxicity:

Tinnitus, hearing impairment (usually reversible), deafness, vertigo, sense of ear fullness
Most common with rapid IV administration; least with oral dosing
Ethacrynic acid has the highest ototoxicity risk among loop diuretics and is reserved for patients who cannot tolerate others
Risk is additive with aminoglycosides, cisplatin, carboplatin, paclitaxel

Hyperuricemia: Initial increase then longer-lived decrease in uric acid excretion; can precipitate gout

Hyperglycemia: Especially with concomitant sulfonylureas

Drug Interactions

Interacting Drug	Effect
NSAIDs / probenecid	Blunted diuretic response (compete for proximal tubule secretion; NSAIDs also reduce PGE₂)
Aminoglycosides, cisplatin, carboplatin, paclitaxel	Synergistic ototoxicity
Digoxin	Hypokalemia increases risk of digoxin-induced arrhythmias
Lithium	Increased plasma lithium levels
Propranolol	Increased propranolol plasma levels
Sulfonylureas	Hyperglycemia
Amphotericin B	Increased nephrotoxicity and electrolyte imbalances
Thiazide diuretics	Synergistic diuresis (can cause profound diuresis) - used therapeutically in diuretic resistance

Diuretic Resistance

The dose-response curve is sigmoidal. It can be shifted downward and rightward (requiring higher doses for same effect) in:

Extracellular volume depletion
Heart failure
Nephrotic syndrome
CKD (organic acid accumulation impairs tubular secretion)
NSAID use
Reduced protein binding (hypoalbuminemia alters pharmacokinetics)

Strategies for resistance: Increasing dose, switching to torsemide (more consistent absorption), adding a thiazide (metolazone + furosemide combination is classic), or IV administration.

Summary Comparison

Feature	Furosemide	Bumetanide	Torsemide	Ethacrynic acid
Sulfonamide	Yes	Yes	Yes	No
Bioavailability	Variable (12-112%)	~80%	~80-90%	~100%
Potency	1x	~40x	~2x	0.7x
Duration	2-3 h	~2 h	4-6 h	~2 h
Ototoxicity	+	+	+	+++ (highest)
Best use in sulfa allergy	No	No	No	Yes

Sources: Goodman & Gilman's The Pharmacological Basis of Therapeutics; Katzung's Basic and Clinical Pharmacology 16th Ed.; National Kidney Foundation Primer on Kidney Diseases 8th Ed.; Braunwald's Heart Disease; Goldman-Cecil Medicine

Raas

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Renin-Angiotensin-Aldosterone System (RAAS)

Overview

The RAAS is the principal hormonal cascade regulating extracellular fluid volume, sodium balance, and blood pressure. It consists of a chain of enzymatic steps - from renin release to angiotensin II (Ang II) generation to aldosterone secretion - that collectively drive vasoconstriction and sodium retention to restore perfusion pressure when it falls.

The Cascade: Step by Step

RAAS cascade - Costanzo Physiology 7th Edition

Fig. 4.33 - Renin-Angiotensin-Aldosterone System (Costanzo Physiology, 7th Ed.)

Step 1 - Renin

Source: Juxtaglomerular (JG) cells (granular cells) in the wall of the afferent arteriole of the kidney, within the juxtaglomerular apparatus (JGA).

Synthesis: Produced as prepro-renin → pro-renin → active renin (340 amino acid glycoprotein) by cleavage of a 43-amino acid N-terminal prosegment.

Prorenin circulates at 80-90% of total; active renin is released by exocytosis on stimulation
Extrarenal tissues (adrenal, ovaries, testes, placenta, retina) also produce prorenin
Plasma renin disappears entirely after nephrectomy

Function: Cleaves angiotensinogen (a liver-derived glycoprotein, MW ~57,000) at the N-terminal to release the decapeptide Angiotensin I (Ang I).

Step 2 - Angiotensin I

A decapeptide with little or no intrinsic biologic activity
Serves solely as substrate for ACE
Can also be converted by aminopeptidases to [des-Asp]-Ang I, then to Ang III by ACE

Step 3 - ACE and Angiotensin II

ACE (Angiotensin-Converting Enzyme, Kininase II):

A dipeptidyl carboxypeptidase located on the luminal surface of vascular endothelial cells throughout the body (especially pulmonary vasculature)
Cleaves a dipeptide from the C-terminus of Ang I → forms the octapeptide Angiotensin II (Ang II)
Also cleaves (inactivates) bradykinin - this is why ACE inhibitors cause bradykinin accumulation and a dry cough
Cannot cleave substrates with a penultimate prolyl residue (so Ang II is not further degraded by ACE)

ACE2 (a homolog):

Carboxypeptidase (removes a single C-terminal amino acid)
Converts Ang I → Ang 1-9 and Ang II → Ang 1-7
Does NOT hydrolyze bradykinin; NOT inhibited by ACE inhibitors
Ang 1-7 acts on the Mas receptor → vasodilation, natriuresis, anti-proliferative effects (counter-regulatory arm)
ACE2 is also the entry receptor for SARS-CoV-2

RAAS pathway including ACE2/Ang1-7/Mas counter-regulatory arm

Full RAAS pathway including classical (black), (pro)renin receptor (red), and counter-regulatory Ang 1-7/Mas axis (blue) - Katzung's Basic and Clinical Pharmacology, 16th Ed.

Control of Renin Release

Renin release is the rate-limiting step of the RAAS - it is the primary determinant of overall system activity.

Stimuli for Renin Release

Mechanism	Signal	Mediators
Macula densa	Decreased NaCl delivery to distal tubule (sensed via NKCC2)	PGE₂, NO (stimulate renin); adenosine (inhibits)
Renal baroreceptor	Decreased stretch of JG cells (low afferent arteriolar pressure)	Decreased Ca²⁺ influx into JG cells → increased renin
Sympathetic nervous system	Beta-1 adrenergic stimulation of JG cells (direct); also indirectly via baroreceptor and macula densa	Norepinephrine → ↑ cAMP → renin release
Low plasma Ang II	Negative feedback removed	Direct AT1R-mediated suppression absent

Intracellular signaling in JG cells:

cAMP is the primary driver: agents that raise cAMP increase renin (beta-agonists, PDE inhibitors, diuretics, vasodilators)
Ca²⁺ is paradoxically inhibitory: unlike most secretory cells, increased intracellular Ca²⁺ in JG cells decreases renin release
cGMP (via ANP, nitric oxide) inhibits renin via cGKII

Inhibitors of Renin Release

Ang II (negative feedback), nitric oxide, aldosterone, endothelin, adenosine, ANP, TNF-α, active Vitamin D, cGKII

Pharmacologic stimulators of renin release

Vasodilators (hydralazine, minoxidil, nitroprusside), beta-agonists, alpha-blockers, diuretics (including furosemide - which reduces NaCl delivery to macula densa), phosphodiesterase inhibitors

Angiotensin II Receptors

Receptor	Location	Effects
AT1R (G-protein coupled)	Vascular smooth muscle, kidney (PT, efferent arteriole), adrenal cortex, heart, brain, liver	Vasoconstriction, Na⁺ retention, aldosterone release, cardiac hypertrophy, fibrosis, proinflammatory
AT2R	Fetal tissues, adrenal medulla, kidney	Vasodilation, natriuresis, anti-proliferative, anti-fibrotic (counter-regulatory)
Mas receptor	Brain, kidney, heart	Ang 1-7 binding → vasodilation, cardioprotection
(Pro)renin receptor (PRR)	Multiple tissues	Non-proteolytic activation of prorenin; downstream ERK1/2 MAP kinase signaling; pro-fibrotic effects

Actions of Angiotensin II

Ang II acts primarily via AT1R:

Vascular

Potent vasoconstrictor of systemic arterioles → ↑ total peripheral resistance (TPR) → ↑ blood pressure
At low doses: preferential efferent arteriolar constriction → maintains GFR by increasing filtration fraction
At high doses: both afferent and efferent constriction → ↓ RBF and GFR
Chronic Ang II → glomerular hypertension → glomerular damage, proteinuria

Renal - Direct

Stimulates Na⁺-H⁺ exchange (NHE3) in proximal tubule → increases Na⁺ and HCO₃⁻ reabsorption
Upregulates Na⁺-K⁺-ATPase at basolateral membrane of proximal tubule
Increases renovascular resistance, decreases medullary blood flow → mediates salt sensitivity

Renal - via Aldosterone

Stimulates aldosterone synthesis and release from adrenal zona glomerulosa
Aldosterone acts on principal cells of distal tubule and collecting duct → ↑ ENaC expression (Na⁺ reabsorption) and ↑ K⁺/H⁺ secretion
Aldosterone's effects require gene transcription and new protein synthesis → slow response (hours to days)

Adrenal

Stimulates aldosterone release (synergistic with hyperkalemia, which is an independent stimulus)

Central Nervous System

Stimulates thirst and salt craving
Stimulates ADH (AVP) secretion from posterior pituitary (via AT1R at the subfornical organ - a circumventricular organ lacking blood-brain barrier)
These effects increase total body water → complement the Na⁺ retention effect

Cardiac / Vascular (Pathologic)

Promotes cardiac hypertrophy (via AT1R, TGF-β pathway)
Induces cardiac and vascular fibrosis, interstitial collagen remodeling
Endothelial dysfunction, increased oxidative stress
These maladaptive effects are mediated locally by tissue RAAS even when systemic Ang II levels are normal

Sympathoadrenal

Augments catecholamine release and potentiates sympathetic activity

Aldosterone

Produced by zona glomerulosa of adrenal cortex
Stimulated by: Ang II, hyperkalemia (direct, synergistic with Ang II), ACTH (minor role)
Acts on principal cells of cortical collecting duct:
- Increases apical ENaC expression → Na⁺ reabsorption
- Increases basolateral Na⁺-K⁺-ATPase
- Net effect: Na⁺ retention, K⁺ excretion, H⁺ excretion (metabolic alkalosis if excess)
Local aldosterone in the heart: induces structural remodeling of interstitial collagen matrix → diastolic dysfunction, ventricular hypertrophy, fibrosis

Systemic vs. Local (Tissue) RAAS

A key modern concept is that there are local RAAS systems in the heart, kidney, brain, and vasculature, independent of the systemic (circulating) RAAS:

Systemic RAAS is most prominent in acute decompensated states (acute HF, acute volume loss)
Local/tissue RAAS dominates in chronic stable conditions (chronic HF, CKD, chronic hypertension)
Local Ang II acts in a paracrine/autocrine manner via locally upregulated angiotensinogen and ACE
This explains why RAAS inhibition remains effective in chronic HF even when circulating levels of Ang II are not markedly elevated

RAAS in Disease States

Heart Failure

RAAS activation is proportional to severity of cardiac dysfunction and serves as a prognostic marker
Initially adaptive: vasoconstriction maintains perfusion
Chronically maladaptive: sodium retention, myocardial remodeling, fibrosis, progressive cardiac and renal dysfunction
Local cardiac Ang II (via AT1R) → TGF-β mediated hypertrophy, fibrosis, reduced coronary flow
Local aldosterone → interstitial fibrosis → systolic and diastolic dysfunction

Hypertension

Ang II is central to BP dysregulation: acts via AT1R to cause systemic vasoconstriction, ↓ medullary blood flow, salt sensitivity
Renal AT1R effects are more critical than extrarenal AT1R in sustained hypertension (cross-transplant experiments)
Prorenin receptor (PRR) signaling also contributes via MAP kinase pathways

CKD

Accumulation of endogenous organic acids impairs tubular secretion of RAAS-blocking drugs
Chronic RAAS activation accelerates glomerulosclerosis and proteinuria

Pharmacologic Blockade of RAAS

Drug Class	Site of Action	Notes
ACE inhibitors (enalapril, lisinopril, ramipril)	Block ACE → ↓ Ang II, ↓ aldosterone, ↑ bradykinin	Bradykinin accumulation → dry cough (10-15%), angioedema
ARBs (losartan, valsartan, candesartan)	Block AT1R directly	No bradykinin effect; no cough; used if ACE-I intolerant
Aldosterone antagonists / MRAs (spironolactone, eplerenone)	Block mineralocorticoid receptor	Potassium-sparing; eplerenone is more selective (fewer androgen side effects)
Direct renin inhibitors (aliskiren)	Block renin activity → ↓ Ang I and Ang II	No evidence of superiority over ACE-I or ARB alone; NOT combined with ACE-I/ARB
Beta-blockers	↓ sympathetic stimulation of JG cells → ↓ renin release	Indirect RAAS suppression

Clinical indications for RAAS blockade: Hypertension, heart failure (HFrEF), post-MI, diabetic nephropathy, proteinuric CKD, left ventricular hypertrophy, primary aldosteronism.

ACE-I/ARB combination: Dual RAAS blockade offers no additional renoprotection over monotherapy in most patients and increases risk of hypotension, hyperkalemia, and AKI - not routinely recommended.

Summary Diagram of the Full Cascade

Low BP / Low Na delivery / Sympathetic stimulation
              ↓
   JG cells → RENIN released
              ↓
   Angiotensinogen (liver) → ANGIOTENSIN I (decapeptide, inactive)
              ↓ [ACE - lung/endothelium]
         ANGIOTENSIN II (octapeptide, highly active)
         ↙              ↓              ↓             ↘
  AT1R                AT1R           AT1R           AT1R
  Vasoconstriction    Proximal       Adrenal         Brain
  ↑TPR, ↑BP          tubule Na⁺     Zona           Thirst + ADH
                      reabsorption   Glomerulosa    ↑Water intake
                                       ↓
                                  ALDOSTERONE
                                       ↓
                            Distal tubule/CD
                            ↑ Na⁺ reabsorption
                            ↓ K⁺/H⁺ excretion
                            ↑ ECF volume → ↑BP

Counter-regulatory arm (ACE2):
  ANG II → [ACE2] → ANG 1-7 → Mas receptor → Vasodilation, natriuresis

Sources: Katzung's Basic and Clinical Pharmacology 16th Ed.; Brenner and Rector's The Kidney; Costanzo Physiology 7th Ed.; Medical Physiology (Boron & Boulpaep); Comprehensive Clinical Nephrology 7th Ed.

Please give about loop diuretics and raas in five marks question type answers raas in a flow chart manner

Here are both topics in concise 5-mark answer format, with RAAS as a flowchart:

Loop Diuretics — 5 Mark Answer

Definition

Loop diuretics are the most potent class of diuretics, acting on the thick ascending limb (TAL) of the loop of Henle. Also called high-ceiling diuretics.

Drugs

Furosemide (most common)
Bumetanide
Torsemide
Ethacrynic acid (only non-sulfonamide - used in sulfa allergy)

Mechanism of Action

Site: Thick ascending limb (TAL) of loop of Henle

Action: Inhibit the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2) on the luminal membrane

Blocks reabsorption of ~25% of filtered Na⁺
Reduces lumen-positive potential → increases Mg²⁺ and Ca²⁺ excretion
Disrupts medullary hypertonicity → impairs water reabsorption even in presence of ADH
Increases PGE₂ synthesis (COX-2 induction) → contributes to diuresis and venodilation
NSAIDs blunt this effect by inhibiting prostaglandin synthesis

Pharmacokinetics

Drug	Oral Bioavailability	Duration
Furosemide	12–112% (variable)	2–3 hours
Torsemide	~80–90% (consistent)	4–6 hours
Bumetanide	~80%	~2 hours
Ethacrynic acid	~100%	~2 hours

All are highly protein-bound → reach tubular lumen via proximal tubule secretion (OAT1/OAT2)
NSAIDs and probenecid compete for this transporter → reduced diuretic effect

Clinical Uses

Acute pulmonary edema (IV furosemide - venodilation + diuresis)
Chronic heart failure
Nephrotic syndrome edema
Hypercalcemia (with IV saline)
Hypertension with GFR <30 mL/min or resistant hypertension
Hyperkalemia, hyponatremia (life-threatening)
CKD-associated edema

Adverse Effects

Hypokalemia → cardiac arrhythmias (especially with digoxin)
Hypomagnesemia
Hypochloremic metabolic alkalosis
Ototoxicity (tinnitus, deafness) - worst with ethacrynic acid and rapid IV use
Volume depletion, hypotension
Hyperuricemia, hyperglycemia

Drug Interactions

Aminoglycosides / cisplatin → additive ototoxicity
Digoxin → hypokalemia → digoxin toxicity
NSAIDs / probenecid → reduced diuretic response
Thiazides → synergistic diuresis (used in diuretic resistance)

RAAS — 5 Mark Answer (Flowchart Format)

Definition

The Renin-Angiotensin-Aldosterone System (RAAS) is the principal hormonal cascade regulating blood pressure, sodium balance, and extracellular fluid volume.

RAAS Flowchart

TRIGGER
─────────────────────────────────────────────────────
↓ Blood pressure / ↓ Na⁺ delivery to macula densa
/ ↑ Sympathetic activity (β1 stimulation)
                        │
                        ▼
              ┌─────────────────┐
              │  JG CELLS       │  ← Juxtaglomerular cells
              │  (Afferent      │     in afferent arteriole
              │   arteriole)    │
              └────────┬────────┘
                       │ releases
                       ▼
                    RENIN
              (aspartyl protease)
                       │
                       │ cleaves
                       ▼
          Angiotensinogen (liver) ──────────────────────────────────────────────►
                       │
                       ▼
              ANGIOTENSIN I
            (decapeptide - INACTIVE)
                       │
                       │  ACE (lung endothelium)
                       │  + bradykinin inactivated here
                       ▼
              ANGIOTENSIN II
             (octapeptide - ACTIVE)
                       │
          ┌────────────┼──────────────┬─────────────────┐
          ▼            ▼              ▼                  ▼
    AT1R on       AT1R on        AT1R in           AT1R in
    Arterioles    Proximal        Adrenal           Brain
                  Tubule          Cortex
          │            │              │                  │
          ▼            ▼              ▼                  ▼
   Vasoconstriction  ↑ Na⁺-H⁺     ALDOSTERONE       ↑ Thirst
   ↑ TPR → ↑ BP     exchange     released           ↑ ADH release
                    ↑ Na⁺ & HCO₃⁻                    ↑ Water retention
                    reabsorption
                                     │
                                     ▼
                          Distal tubule / Collecting duct
                                     │
                          ┌──────────┴──────────┐
                          ▼                     ▼
                   ↑ ENaC activity        ↑ Na⁺-K⁺-ATPase
                   ↑ Na⁺ reabsorption     ↑ K⁺ / H⁺ excretion
                          │
                          ▼
                   ↑ ECF volume → ↑ Blood volume
                          │
                          ▼
                 ┌──────────────────┐
                 │  ↑ BLOOD         │
                 │  PRESSURE        │
                 │  (RESTORED)      │
                 └──────────────────┘
                          │
                          ▼ (negative feedback)
              ↑ Ang II suppresses further renin release
              ↑ BP suppresses baroreceptor-mediated renin release


COUNTER-REGULATORY ARM (ACE2 pathway):
─────────────────────────────────────
Ang II ──[ACE2]──► Ang 1-7 ──► Mas receptor
                                     │
                                     ▼
                        Vasodilation / Natriuresis
                        (opposes Ang II effects)

Key Points to Remember

Component	Key Fact
Renin	Rate-limiting step; released from JG cells
Angiotensinogen	Substrate from liver; substrate concentration rarely rate-limiting
ACE	Lung endothelium; also inactivates bradykinin
Ang II	Acts via AT1R (harmful) and AT2R (protective/counter-regulatory)
Aldosterone	Slow response (hours-days); gene transcription required
ACE2	Converts Ang II → Ang 1-7 (protective); entry point for SARS-CoV-2

Pharmacologic Blockade (for exam - 1 liner each)

Drug Class	Example	Site Blocked
ACE inhibitors	Enalapril, Ramipril	Block ACE → ↓ Ang II, ↑ bradykinin (→ cough)
ARBs	Losartan, Valsartan	Block AT1R directly; no cough
MRAs	Spironolactone, Eplerenone	Block aldosterone receptor; K⁺-sparing
Direct renin inhibitor	Aliskiren	Blocks renin activity
Beta-blockers	Metoprolol	↓ β1 stimulation → ↓ renin release

Adverse Effects of RAAS Blockade (Exam Favourite)

ACE inhibitors: Dry cough (bradykinin), hyperkalemia, angioedema, ↑ creatinine (especially with bilateral renal artery stenosis)
ARBs: Hyperkalemia, ↑ creatinine; no cough
Spironolactone: Gynecomastia, hyperkalemia
Aliskiren: NOT combined with ACE-I or ARB (risk of hypotension, AKI, hyperkalemia)

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