Pharmacology Notes

Owner: Samantha Anne Nicole S. Sanchez

DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

CHAPTER 25: DIURETICS ○​ Small molecules:

■​ Ions
■​ Water
■​ Glucose
■​ Cellular waste
products
●​ What cannot pass:
○​ Large molecules such as
plasma proteins

ELECTROLYTE AND ACID-BASE

REGULATION

Importance of Electrolytes

●​ Essential ions for body function:

○​ Sodium (Na⁺)
○​ Potassium (K⁺)
○​ Chloride (Cl⁻)

Functions
INTRODUCTION: KIDNEYS AND DIURETICS
●​ Maintain stability of cell membranes
Primary Functions of the Kidneys
Acid-Base Balance
●​ Maintain:
○​ Water balance ●​ Bicarbonate ions (HCO₃⁻):
○​ Electrolyte balance ○​ Act as buffers
○​ Acid–base balance ○​ Maintain blood pH between
7.35 – 7.45
Renal Blood Flow

●​ Kidneys receive approximately:

○​ 25% of cardiac output
RENAL FUNCTION IN HOMEOSTASIS

Filtration Process ●​ Kidneys must:

○​ Reabsorb essential
●​ As blood flows through the kidneys: substances
○​ Substances are continuously ○​ Excrete waste products
filtered
●​ What can pass through renal
Balance Between Processes
membranes:
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

●​ Renal reabsorption + excretion → 1.​ Increase glomerular filtration

urine formation 2.​ Decrease renal reabsorption
of water and sodium
Pathophysiology
Physiologic Effect
●​ When this balance is disrupted:
○​ Kidneys fail to regulate water ●​ ↓ Water reabsorption → ↑ urine
and ions volume and flow (diuresis)
○​ Fluid accumulates in tissues
→ edema

CLASSES OF DIURETICS

CLINICAL INDICATIONS FOR DIURETIC USE Overview

Definition of Diuretics ●​ Diuretics are classified into six major

groups:
●​ Drugs that: ○​ Osmotic agents
○​ Increase urine production ○​ Carbonic anhydrase
○​ Promote excretion of water inhibitors
and sodium ○​ Thiazide and thiazide-like
diuretics
Main Clinical Uses ○​ Organic acids
○​ Potassium-sparing diuretics
●​ Anuria (absence of urine production) ○​ ADH antagonists
●​ Hypertension
●​ Edema General Mechanism

●​ All diuretics:
○​ Inhibit sodium and/or water
Conditions Associated with Edema reabsorption in the kidneys

●​ Chronic heart failure (CHF) Key Concept

●​ Liver cirrhosis
●​ Brain inflammation ●​ Different classes act at different sites
●​ Eye conditions (e.g., glaucoma) along the nephron
●​ Kidney inflammation (nephritis) ●​ Therefore:
○​ The intensity of diuresis
varies between drug classes

Mechanism of Action of Diuretics

●​ Two main ways diuretics increase

urine output:
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

FACTORS AFFECTING DIURETIC ●​ Allows:

EFFECTIVENESS ○​ Reabsorption of nutrients,
water, and electrolytes into
●​ The intensity of diuresis depends on: the blood
○​ Extent of sodium ion ○​ Elimination of metabolic
excretion into urine waste products via urine

Implication

●​ More sodium excretion → more water Functional Unit of the Kidney: Nephron
follows → greater diuresis
●​ Kidneys contain millions of nephrons
●​ Each nephron consists of:
○​ Glomerulus
○​ Proximal convoluted tubule
CLINICAL NOTE (PCT)
○​ Loop of Henle
●​ Understanding renal tubule function ○​ Distal convoluted tubule
is essential to: (DCT)
○​ Determine the most effective ○​ Collecting duct
diuretic
○​ Predict adverse effects of
diuretic therapy

Processes of Urine Formation

Urine is formed through three main

processes:

●​ Filtration
●​ Reabsorption
●​ Secretion

Additional Function of Nephrons: Blood

Pressure Regulation
RENAL PHYSIOLOGY AND CONDITIONS
●​ Achieved through:
ASSOCIATED WITH RENAL DYSFUNCTION
○​ Reabsorption of sodium and
water
URINE FORMATION ○​ Activity of juxtaglomerular
(JG) cells

Purpose of Urine Formation Juxtaglomerular (JG) Cells

●​ Essential for normal body function ●​ Located near the glomerulus

Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

●​ Respond to changes in blood ●​ Amino acids

pressure ●​ Electrolytes

Renin-Angiotensin-Aldosterone System What is Retained

(RAAS)
●​ Red blood cells (RBCs)
●​ When blood volume is low: ●​ Plasma proteins
○​ JG cells secrete renin
○​ Renin → stimulates
production of angiotensin
○​ Angiotensin:
■​ Causes TUBULAR FUNCTIONS
vasoconstriction → ↑
blood pressure
Renal Tubules
■​ Stimulates
aldosterone secretion ●​ Include:
●​ Aldosterone: ○​ Proximal tubule
○​ Promotes sodium and water ○​ Loop of Henle
retention ○​ Distal tubule
○​ Increases blood volume and
blood pressure
●​ When blood pressure is adequate: Functions
○​ Renin, angiotensin, and
●​ Reabsorption:
aldosterone secretion
○​ Return substances from
decrease
tubular fluid to blood
●​ Secretion:
○​ Transfer substances from
blood into tubular fluid
FILTRATION

Site of Filtration
Tubular Reabsorption
●​ Occurs in the glomerulus
●​ Most filtered substances are
reabsorbed
Mechanism
●​ Approximately 99% of sodium is
reabsorbed
●​ High blood pressure in glomerular
capillaries forces:
○​ Small molecules into the Importance of Sodium
filtrate
●​ Principal extracellular cation
●​ Creates osmotic gradient that drives
What Passes Through
water reabsorption

●​ Vitamins
Key Principle
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

●​ Water balance depends on sodium

reabsorption
Water Reabsorption

●​ Water follows sodium due to osmotic

Mechanisms of Sodium Reabsorption gradient

1. Cation Exchange (PCT and DCT) Primary Sites of Water Reabsorption

●​ Sodium ions (Na⁺) exchanged for ●​ Proximal convoluted tubule

hydrogen ions (H⁺) ●​ Collecting ducts

Carbonic Anhydrase System Role of ADH

●​ CO₂ + H₂O → Carbonic acid (H₂CO₃) ●​ Antidiuretic hormone (ADH):

●​ H₂CO₃ → H⁺ + HCO₃⁻ ○​ Opens aquaporins in
●​ Hydrogen ions: collecting ducts
○​ Secreted into tubular fluid in ○​ Increases water reabsorption
exchange for sodium ○​ Decreases urine volume
●​ Bicarbonate ions:
○​ Reabsorbed into blood via
peritubular capillaries
Clinical Importance

●​ Diuretics work by:

2. Potassium Secretion (DCT) ○​ Inhibiting sodium and water
reabsorption
●​ Potassium ions (K⁺) secreted in ○​ Increasing urine output
exchange for sodium (diuresis)
●​ Regulated by aldosterone
●​ Aldosterone:
○​ Binds to receptors in distal
tubules
○​ Promotes K⁺ secretion into TUBULAR SECRETION
urine
○​ Enhances Na⁺ reabsorption
Substances Secreted

●​ Hydrogen ions (H⁺)

●​ Potassium ions (K⁺)
3. Sodium-Chloride Transport (Loop of ●​ Weak acids
Henle) ●​ Weak bases

●​ Sodium reabsorbed along with

chloride ions (Cl⁻)
●​ Chloride is actively reabsorbed →
sodium follows Functions of Tubular Secretion
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

1. Acid-Base Regulation CONDITIONS ASSOCIATED WITH RENAL

DYSFUNCTION
●​ Hydrogen ion secretion acidifies
urine (pH < 7)
Causes of Renal Dysfunction
●​ Maintains blood pH between 7.35 –
7.45 ●​ Renal diseases:
○​ Nephritis
Carbonic Anhydrase Role ○​ Glomerulonephritis
○​ Pyelonephritis
●​ Produces:
●​ Cardiovascular disorders:
○​ H⁺ (secreted into urine)
○​ Chronic heart failure (CHF)
○​ HCO₃⁻ (reabsorbed into blood)
○​ Hypertension
●​ Bicarbonate:
○​ Shock
○​ Buffers acids in blood (e.g.,
lactic acid)
Mechanisms

Clinical Implication ●​ Disease → reduced renal tissue

function OR reduced blood flow
●​ Impaired bicarbonate production →
●​ Result → decreased kidney filtration
metabolic acidosis

2. Excretion of Weak Acids and Bases Consequences of Renal Dysfunction

●​ Weak acids: 1. Reduced Urine Output

○​ Uric acid, aspirin,
barbiturates, penicillin ●​ Oliguria → decreased urine volume
●​ Weak bases: ●​ Anuria → no urine production
○​ Opioid analgesics,
antihistamines 2. Accumulation of Waste

●​ Toxic substances accumulate in

Drug Excretion blood

●​ Many drugs are eliminated via

3. Uremia
proximal tubule secretion
●​ Compete with endogenous waste
●​ Accumulation of nitrogenous waste
products for transport sites
products
●​ Competition may:
●​ Also called toxemia
○​ Alter drug excretion
○​ Cause drug accumulation in
blood
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

Fluid Retention Effects

Hypertension

●​ Caused by:
○​ Sodium retention
○​ Increased blood volume
●​ Mechanism:
○​ Sodium creates osmotic
gradient → water retention →
↑ blood pressure

Edema

●​ Fluid accumulation in extracellular

spaces
●​ Common in:
○​ Legs and feet
●​ Caused by:
○​ Sodium and water retention

Systemic Impact

●​ Increased fluid volume:

○​ Strains heart
○​ Worsens kidney function
○​ Can lead to progression of
renal and cardiac failure
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

●​ Stimulate urine flow in:

○​ Anuria
○​ Oliguria
●​ Prevent irreversible renal damage

Other Clinical Indications

●​ Acute renal failure

●​ Cardiovascular surgeries with
compromised renal function
●​ Drug toxicity or overdose
○​ Promotes renal excretion of
toxins by increasing urine
flow
●​ Cerebral edema
●​ Glaucoma
○​ Reduces:
■​ Intracranial pressure
■​ Intraocular pressure
■​ Localized swelling
and edema

Clinical Limitation

●​ Route of administration and mild

diuretic intensity limit widespread
OSMOTIC DIURETICS
use

Clinical Indications

Common Osmotic Diuretics

MECHANISM OF ACTION
●​ Glycerin
●​ Isosorbide Basic Principle
●​ Mannitol
●​ Urea ●​ Osmotic diuretics:
○​ Are filtered by the glomerulus
○​ Are NOT reabsorbed by renal
Most Frequently Used
tubules
○​ Cannot penetrate cell
●​ Mannitol (Osmitrol)
membranes

Mannitol
Administration

Primary Uses ●​ Must be given intravenously

Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

Osmotic Effect Common Side Effects

●​ After entering circulation: ●​ Nausea

○​ Attract fluid from edematous ●​ Dizziness
tissues into the bloodstream ●​ Headache
●​ Chills
Renal Tubule Effect

●​ Become trapped in the tubular lumen

●​ Create an osmotic gradient Serious Adverse Effect
●​ Water moves toward the diuretic
molecules ●​ Expansion of plasma volume due to
osmotic action
Result
Clinical Consequence
●​ Water is:
●​ Increased cardiac workload
○​ Not reabsorbed
●​ Risk of strain on heart function
○​ Excreted in urine along with
the drug
High-Risk Patients
Electrolyte Effects
●​ Patients with:
○​ Congestive heart failure (CHF)
●​ No significant effect on sodium
○​ Impaired cardiac function
reabsorption
●​ No major changes in:
○​ Electrolyte balance
○​ Acid-base balance
CONTRAINDICATIONS
Intensity of Diuresis
Mannitol should NOT be used in:
●​ Produces mild diuresis
●​ Chronic edema due to cardiovascular
insufficiency
Routes of Administration
●​ Pulmonary edema
●​ Active intracranial bleeding
●​ Mannitol and urea:
○​ Intravenous
●​ Glycerin and isosorbide: Reason
○​ Oral
○​ Duration of diuresis: up to 6 ●​ Plasma volume expansion may
hours worsen:
○​ Cardiac function
○​ Fluid overload conditions
○​ Intracranial pressure
dynamics
ADVERSE EFFECTS
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

●​ Carbonic anhydrase is involved in

aqueous humor formation
●​ Inhibition → ↓ aqueous humor
production
●​ Result:
○​ ↓ intraocular pressure
○​ ↓ edema and pain

Administration

●​ IV route may be used for:

○​ Rapid reduction of intraocular
pressure
●​ Can be combined with:
○​ Miotics
CARBONIC ANHYDRASE INHIBITORS ○​ Osmotic diuretics

Common Drugs

●​ Acetazolamide (Diamox) Neurologic Use

●​ Methazolamide
●​ Used in epilepsy:
○​ Petit mal seizures
○​ Unlocalized seizures

CLINICAL INDICATIONS Mechanism

Primary Uses ●​ Induces metabolic acidosis → ↓

neuronal excitability → ↓ seizure
●​ Adjunct treatment in: activity
○​ Congestive heart failure (CHF)
○​ Drug-induced edema

Other Uses

Ophthalmic Use (Glaucoma) Acute Mountain Sickness

●​ Used in: ●​ Used for prevention and treatment

○​ Chronic simple (open-angle) ●​ Occurs due to:
glaucoma ○​ Rapid ascent → inadequate
○​ Narrow-angle (angle-closure) adaptation to low oxygen
glaucoma
Symptoms Relieved
Mechanism in Eye
●​ Oxygen deficit
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

●​ Muscle weakness Sodium Reabsorption

●​ Cramping
●​ Headache ●​ ↓ H⁺ available for Na⁺ exchange
●​ ↓ sodium reabsorption
Dosing
Outcome
●​ 500–1000 mg/day
●​ Taken: ●​ ↑ sodium excretion
○​ 48 hours before ascent ●​ ↑ water excretion → diuresis
○​ Continued after ascent

ADDITIONAL RENAL EFFECTS

Clinical Limitation

●​ Produces adequate diuresis Potassium Balance

●​ But largely replaced by other
diuretics for edema ●​ Reduced H⁺ exchange →
compensatory ↑ K⁺ exchange
●​ ↑ potassium secretion in distal
tubules

MECHANISM OF ACTION Result

Primary Action ●​ Hypokalemia

●​ Inhibits carbonic anhydrase (CAH)

enzyme
Acid-Base Effects
Normal Role of CAH
Bicarbonate Loss
●​ CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃⁻
●​ Occurs in: ●​ Sodium excreted with bicarbonate
○​ Proximal convoluted tubule ●​ Leads to:
(PCT) ○​ Alkaline urine (↑ pH)
○​ Distal convoluted tubule
(DCT) Blood Changes

●​ ↓ bicarbonate → ↓ buffering capacity

Effects of Inhibition Result

●​ ↓ production of: ●​ Metabolic acidosis

○​ Hydrogen ions (H⁺)
○​ Bicarbonate ions (HCO₃⁻) Type
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

●​ Hyperchloremic metabolic acidosis ●​ Start with lowest dose → titrate

○​ H⁺ retained with Cl⁻ upward
●​ IM route:
○​ Avoid (painful due to alkaline
solution)
●​ IV route:
ROUTE OF ADMINISTRATION ○​ Used for rapid ocular
pressure reduction
Absorption

●​ Well absorbed orally

ADVERSE EFFECTS
Metabolism

●​ Not metabolized Common

●​ Drowsiness
Excretion ●​ Anorexia
●​ Gastrointestinal distress
●​ Excreted unchanged by kidneys
●​ Headache
●​ Depression
Renal Handling ●​ Allergic rash
●​ Acidosis
●​ Weak acids
●​ Secreted via proximal convoluted
tubules
Electrolyte/Metabolic Effects

●​ Hypokalemia
Special Pharmacologic Note ●​ Hyperuricemia

●​ In metabolic acidosis: Hyperuricemia

○​ Drug excretion increases
○​ Diuretic effect decreases ●​ ↑ uric acid due to reduced excretion
●​ Risk:
Clinical Implication ○​ Gout (especially in
predisposed patients)
●​ Considered a refractory diuretic
○​ Effect diminishes when
acid-base balance is altered

CONTRAINDICATIONS

Administration Notes Avoid in Patients with

●​ Metabolic acidosis:
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

○​ Renal failure ●​ Combined with loop diuretics

○​ Severe respiratory acidosis ●​ Effects:
○​ ↑ diuresis
Reason ○​ ↑ sodium & water removal
○​ ↓ volume workload on the
●​ Drug worsens acidosis heart

Use with Caution / Avoid in

📌 General Properties
●​ Not chemically related BUT:
●​ Glaucoma patients with:
○​ Same pharmacologic action
○​ Renal disease
in renal tubules
○​ Mental depression
●​ Orally administered
○​ Electrolyte imbalance
●​ Common drugs:

💊 THIAZIDE & THIAZIDE-LIKE DIURETICS ○​ Chlorothiazide (Diuril)

○​ Chlorthalidone
○​ Metolazone (Zaroxolyn)

📌 Clinical Indications
●​ Largest group of diuretics ⚙️ Mechanism of Action
●​ Widely used for:
○​ Edema with hypertension ●​ Originally designed as carbonic
○​ Edema of any cause: anhydrase inhibitors
■​ CHF ○​ BUT only weak CA inhibitors
■​ Renal disease ●​ Main action:
●​ Particularly useful in: ○​ Inhibit Na⁺ transport in distal
○​ Mild to moderate nephron
hypertension
■​ ↓ plasma volume
■​ Relax vascular
🧪 Effects on Electrolytes & Acid-Base
⏱️
smooth muscle
●​ Effects:
●​ ↑ sodium excretion → intense
○​ Diuretic effect → immediate
diuresis
○​ Antihypertensive effect → 4–6
●​ ↑ chloride excretion
weeks
●​ ↑ potassium excretion

➡️ Results:
💡 Special Use in Heart Failure ●​ Hypokalemia
●​ Hypochloremic alkalosis
●​ Example: metolazone
●​ Used in refractory heart failure
(systolic dysfunction)
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

❗ Important Property ●​ Hyperuricemia

○​ Risk for gout
●​ NOT refractory ●​ Hyperglycemia

⚠️
○​ Diuresis continues even in ○​ Due to ↓ glucose utilization
alkalosis ○​ Can worsen diabetes

🧬 Additional Effects 💪 Musculoskeletal:

🧂 Sodium: ●​ Muscle cramps / spasms
○​ Due to electrolyte loss
●​ Can cause:
○​ Hyponatremia (especially in
older adults)
🫀 Lipid Effects:
🦴 Calcium: ●​ Short-term use:
●​ ↓ calcium excretion ○​ ↑ total cholesterol
●​ Mild ↑ serum calcium (no ○​ ↑ LDL
hypercalcemia) ○​ ↑ triglycerides
●​ Controlled by parathyroid gland ○​ Dose-dependent
●​ ↓ bone resorption ●​ Mechanism:

➡️ Possible benefit:
○​ Volume depletion triggers:
■​ Sympathetic nervous
system
●​ Bone-saving effect (osteoporosis) ■​ Renin-angiotensin-ald
osterone system
●​ Long-term use:

⚠️ Adverse Effects ●​ ❗
○​ Minimal lipid changes
Exception:

💧 Fluid & BP Effects: ○​ Indapamide → no effect on

lipid profile

●​ ↓ plasma volume → ↓ blood pressure

●​ Orthostatic hypotension
○​ Sudden BP drop when
standing
🧴 Hypersensitivity:
○​ Dizziness ●​ Skin rashes
○​ Lightheadedness
○​ Fainting

🍽️ Other Adverse Effects:

⚡ Electrolyte & Metabolic: ●​ Nausea
●​ Diarrhea
●​ Hypokalemia ●​ Constipation
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

●​ Anorexia ○​ Peripheral edema

●​ Headache ○​ Pulmonary edema
●​ Erectile dysfunction
Common Conditions Treated

🧬 Renal Effects: ●​ Congestive heart failure (CHF)

●​ Liver cirrhosis
●​ Renal disease
●​ ↑ blood urea nitrogen (BUN)
●​ ↑ serum creatinine Special Drug Use

●​ Ethacrynic acid

📌 Clinical Note ○​ Used for:

■​ Short-term
management of:
●​ Adverse effects depend on: ■​ Ascites due to
○​ Patient’s condition malignancy
○​ Drug dose ■​ Lymphedema
●​ Usually resolved by:
○​ Reducing dose
Route of Administration
○​ Stopping drug
●​ Parenteral administration indicated
when:
○​ Rapid response is needed
○​ GI absorption is impaired
○​ Oral administration is not
feasible

💊 ORGANIC ACID (LOOP) DIURETICS — ⚙️ Mechanism of Action

COMPLETE TRANS
Common Loop Diuretics

📌 Clinical Indications ●​
●​
Bumetanide
Ethacrynic acid (Edecrin)
●​ Furosemide (Lasix)
●​ Organic acid diuretics have: ●​ Torsemide (Demedex)
○​ Greater diuretic action than
thiazides Examples

Primary Uses ●​ Furosemide

●​ Relief of edema in patients who are

resistant to thiazide diuretics
●​ Severe edema conditions: Site of Action
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

●​ Loop of Henle ○​ Water removal via diuresis

●​ Result:
○​ ↓ workload on the failing heart

Mechanism Commonly Used Drugs

●​ Inhibit sodium (Na⁺) and chloride (Cl⁻) ●​ Furosemide

transport in the loop of Henle ●​ Ethacrynic acid
●​ Result:
○​ Massive loss of:
■​ Sodium
■​ Chloride Combination Therapy
■​ Water
●​ Loop diuretics may be combined
with:
○​ Thiazides (e.g.,
Physiologic Effects chlorothiazide, metolazone)
●​ Purpose:
●​ Produces intense diuresis ○​ Overcome diuretic resistance
●​ Leads to: ○​ Enhance diuresis
○​ Hypochloremic alkalosis
○​ Hypokalemia (possible)

⚠️ Note on Combination Therapy

Important Property ●​ Produces synergistic diuretic effect
●​ Increases risk of:
●​ Not refractory: ○​ Adverse reactions
○​ Continue to produce diuresis
even in acid-base imbalance

🧬 Pharmacokinetics
❤️ Clinical Use in Heart Failure ●​ Highly protein-bound
○​ ↑ risk of drug interactions
●​ Heart failure (CHF) occurs when: (protein displacement)
○​ Ventricles cannot fill or eject ●​ Metabolism:
blood effectively ○​ Partially metabolized in liver
●​ Excretion:
In Systolic Dysfunction ○​ Excreted in urine

●​ Heart cannot eject sufficient blood

Role of Loop Diuretics ⚠️ Adverse Effects

●​ Promote:
Similar to Thiazides
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

●​ Nausea ●​ Anuria (no urine production)

●​ Hypotension (due to plasma volume ●​ Severe electrolyte depletion
contraction)
●​ Hypokalemia Management Before Use:
●​ Hyperuricemia
●​ Hyperglycemia ●​ Correct underlying conditions first
○​ Due to ↓ insulin secretion before administering loop diuretics

Ototoxicity ⚠️ Safety Warning

●​ Hearing loss may occur ●​ Loop diuretics carry a boxed warning
○​ Alerts clinicians about their
Important Drug Interaction potency and risk of severe
fluid/electrolyte imbalance
●​ Should NOT be used with
aminoglycoside antibiotics:
○​ Amikacin
○​ Kanamycin
○​ Neomycin
○​ Streptomycin

➡️ Reason:
●​ Aminoglycosides potentiate
ototoxicity

💧 Diuretic Intensity Warning

●​ Can cause:
○​ Profound diuresis
○​ Severe water and electrolyte
depletion

➡️ Requires:
●​ Careful medical supervision
●​ Individualized dosing

🚫 Contraindications
POTASSIUM-SPARING DIURETICS
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

Clinical Indications ●​ Common:

○​ Nausea
●​ Used in combination with loop or ○​ Diarrhea
thiazide diuretics to manage edema ○​ Hyperkalemia
●​ Prevent or correct hypokalemia induced ●​ Hormonal effects:
by other diuretics ○​ Spironolactone and
●​ Indicated for patients who cannot triamterene may cause
tolerate oral potassium supplements gynecomastia
●​ Spironolactone and triamterene: ●​ Hyperkalemia risk:
○​ Used as adjuncts in ○​ More likely in:
hypertension therapy (often ■​ Renal impairment
lifelong treatment) ■​ Diabetes mellitus
○​ Added to prevent hypokalemia ■​ Older adults
from thiazide or thiazide-like ○​ Risk increases if potassium
diuretics supplements or
●​ Spironolactone: potassium-rich diets are used
○​ Used in primary ●​ Monitoring:
hyperaldosteronism to reduce ○​ Serum potassium must be
potassium loss closely monitored, especially:
■​ At initiation
Mechanism of Action ■​ During dose
adjustments
●​ Drugs: amiloride (Midamor), ■​ During illness affecting
spironolactone (Aldactone), triamterene renal function
(Dyrenium) ●​ Amiloride boxed warning:
●​ Site of action: ○​ Hyperkalemia occurs in ~10%
○​ Distal convoluted tubules when used alone
●​ General effect: ○​ Risk reduced to ~1–2% when
○​ Inhibit potassium secretion → combined with thiazides in
potassium retention appropriate patients
○​ Produce mild diuresis without ●​ Spironolactone warning:
major acid–base disturbance ○​ Long-term high-dose animal
●​ Spironolactone: studies showed tumor
○​ Aldosterone receptor antagonist development → use within
○​ Blocks aldosterone → inhibits recommended conditions only
sodium reabsorption and
potassium excretion
●​ Amiloride and triamterene: ADH ANTAGONISTS AND MISCELLANEOUS
○​ Not aldosterone antagonists DIURETICS
○​ Alter distal tubular membrane
function → reduce sodium ADH (Antidiuretic Hormone) Physiology
reabsorption and prevent
●​ ADH regulates water balance by
potassium secretion
controlling water loss in urine
Adverse Effects ●​ Osmoreceptors in the hypothalamus
monitor plasma sodium
concentration
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

●​ Normal serum sodium: 135–145 ○​ Block ADH receptors in renal

mEq/L collecting ducts
●​ Hypertonic plasma (>145 mEq/L): ○​ Promote excretion of free
○​ Triggers ADH secretion from water (aquaresis) without
posterior pituitary electrolyte loss
●​ ADH acts on kidneys: ●​ Therapeutic effect:
○​ Binds receptors in collecting ○​ Increase serum sodium
ducts concentration
○​ Stimulates synthesis of water ○​ Used in conditions with water
channels (aquaporins) retention and hyponatremia
○​ Increases water reabsorption
into blood Examples and Receptor Activity
●​ Result:
○​ Decreased plasma osmolarity ●​ Conivaptan (Vaprisol):
○​ Urine becomes more ○​ Blocks V1a (vascular smooth
concentrated muscle) and V2 (renal
○​ Negative feedback inhibits collecting ducts) receptors
further ADH secretion ○​ Administered intravenously
●​ Hypotonic plasma (<135 mEq/L): ●​ Tolvaptan (Samsca):
○​ Suppresses ADH secretion ○​ Selective V2 receptor
●​ Conditions affecting ADH regulation: antagonist
○​ Water retention states: ○​ Oral administration
cirrhosis, cardiac failure,
severe vomiting, diarrhea Dosage / Administration
●​ Clinical note:
○​ Hyponatremia may occur in ●​ Conivaptan:
hospitalized or long-term care ○​ 20 mg IV loading dose
patients due to altered renal ○​ Followed by 20 mg infusion
function and medications over 24 hours
○​ Management may include: ●​ Tolvaptan:
■​ Reducing water intake ○​ Initial dose: 15 mg PO once
■​ Adjusting diuretic daily
therapy ○​ May increase to 30–60 mg/day
■​ Using diuretics that as needed
remove free water
Pharmacokinetics
without significant
sodium loss
●​ Highly protein bound (~99%)
●​ Metabolized in the liver
●​ Excreted primarily in feces

ADH Antagonists (Vaptans)

Adverse Effects

●​ Drug class: vasopressin (ADH)

●​ Thirst
receptor antagonists
●​ Dry mouth
●​ Mechanism:
●​ Increased daytime urination
●​ Conivaptan-specific:
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

○​ Injection site reactions ○​ Active ingredient in some

○​ Headache over-the-counter diuretic
○​ Hypotension products
○​ Vomiting
○​ Constipation Adverse Effects

Drug Interactions ●​ CNS stimulation

●​ Hypotension
●​ Avoid concurrent use with: ●​ Headache
○​ Ketoconazole
○​ Itraconazole PREFERRED TREATMENT, ADVERSE
○​ Clarithromycin EFFECTS, AND DRUG INTERACTIONS
○​ Ritonavir
○​ Indinavir
●​ Reason:
○​ These inhibit hepatic CYP450
enzymes → increase vaptan Preferred Treatment
levels
●​ ADH antagonists
○​ Indicated for euvolemic and
hypervolemic hyponatremia
in hospitalized patients
Xanthine Diuretics
●​ Carbonic anhydrase inhibitors
Overview ○​ Used in:
■​ Glaucoma
●​ Naturally occurring mild diuretics ■​ Edema with alkalosis
●​ Examples: ■​ Mountain sickness
○​ Caffeine ●​ Loop diuretics
○​ Pamabrom ○​ Used in:
○​ Theobromine ■​ Pulmonary edema
○​ Theophylline ■​ Peripheral edema
■​ Hypertension
Mechanism of Action ■​ Acute hypercalcemia
■​ Hyperkalemia
●​ Increase renal blood flow ■​ Acute renal failure
●​ Increase glomerular filtration rate ●​ Thiazide diuretics
(GFR) ○​ Preferred for:
●​ Enhance urine formation ■​ Hypertension
●​ Result: ■​ Mild heart failure
○​ Mild diuresis ■​ Nephrolithiasis
■​ Nephrogenic diabetes
Clinical Use insipidus
●​ Osmotic diuretics
●​ Often used in combination with other ○​ Used to:
diuretics ■​ Improve renal failure
●​ Caffeine: due to increased load
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

(rhabdomyolysis, ■​ Oral potassium

chemotherapy) supplements (e.g.,
■​ Reduce intracranial K-Lyte, Slow-K) in
pressure severe cases
■​ Decrease intraocular ■​ Potassium-sparing
pressure in glaucoma diuretics as adjunct
●​ Potassium-sparing diuretics therapy
○​ Used for: ○​ Note: Potassium supplements
■​ Hypokalemia caused may cause GI irritation →
by other diuretics reduced adherence
■​ Post–myocardial ●​ Orthostatic hypotension and
infarction dehydration
○​ Spironolactone: ○​ Caused by loss of salt and
■​ Specifically indicated water → plasma volume
for aldosteronism of contraction
any cause ○​ Can lead to:
■​ Dizziness
■​ Fainting
○​ Monitoring:
Adverse Effects ■​ Vital signs
■​ Blood pressure
●​ Most diuretics (especially potent ■​ Urine output
types): ○​ Patients may require dietary
○​ Cause electrolyte and sodium restriction
acid–base disturbances with ●​ Weight loss and dehydration
chronic use ○​ Due to excessive fluid loss
○​ Require periodic monitoring from potent diuretics
of serum electrolytes ●​ Blood glucose effects
○​ Potassium levels are ○​ Diabetics require periodic
particularly important glucose monitoring
●​ Hypokalemia ●​ Sulfonamide sensitivity
○​ Occurs in ~10–40% of ○​ Patients sensitive to
patients on chronic diuretic sulfonamides may react to:
therapy ■​ Furosemide
○​ Effects: ■​ Thiazide diuretics
■​ Muscle weakness ●​ Overdose
■​ Fatigue ○​ Effects include:
■​ Cardiac arrhythmias ■​ Hypotension,
○​ Prevention/management: dizziness, drowsiness
■​ Potassium-rich foods (plasma volume
(e.g., bananas, orange depletion)
juice, dates, figs, ■​ Confusion, muscle
prunes, apricots, weakness, GI
raisins, potatoes, disturbances
grapefruit and prune (electrolyte
juice) imbalance)
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

○​ No specific antidote ○​ Interact with CYP450

○​ Management: inhibitors:
■​ Gastric lavage or ■​ Midazolam,
emesis if appropriate simvastatin →
■​ Maintain hydration increased levels
and electrolytes ■​ Ketoconazole,
parenterally itraconazole,
■​ Support respiration if clarithromycin,
needed ritonavir, indinavir →
increase vaptan levels

Drug Interactions and Incompatibilities

Parenteral Administration and Compatibility
●​ Digoxin
○​ Diuretic-induced hypokalemia ●​ Preferred route:
↑ digoxin toxicity ○​ Intravenous infusion or slow
○​ May lead to arrhythmias IV injection
○​ Potassium balance must be ●​ Intramuscular route:
maintained ○​ Avoid due to pain and
●​ Lithium irritation
○​ Diuretics ↓ renal clearance of ●​ Compatibility concerns:
lithium ○​ Avoid mixing drugs that may
○​ ↑ risk of lithium toxicity cause:
●​ Carbonic anhydrase inhibitors ■​ Precipitation
○​ Potentiates potassium ■​ Complex formation
depletion with corticosteroids ■​ Discoloration
○​ ↑ excretion of acidic drugs ○​ Examples of incompatibilities:
●​ CNS depressants and ■​ Mannitol:
antihypertensives ■​ Do not mix
○​ Alcohol, antihypertensives, with whole
barbiturates, opioids: blood
■​ Increase risk of (agglutination
orthostatic risk)
hypotension with ■​ May interact
thiazides and loop with cisplatin
diuretics (complex
●​ Diazoxide formation)
○​ With thiazides → potentiates: ■​ Chlorothiazide:
■​ Hypotension ■​ Incompatible
■​ Hyperglycemia with amikacin,
■​ Hyperuricemia chlorpromazin
●​ Aminoglycosides e, codeine,
○​ Increase risk of ototoxicity insulin,
with loop diuretics methadone,
●​ ADH antagonists (vaptans) morphine,
Pharmacology Notes
Owner: Samantha Anne Nicole S. Sanchez
DO NOT DISTRIBUTE WITHOUT MY CONSENT!!

procaine, ○​ Advise slow position changes

promethazine, to prevent orthostatic
streptomycin, hypotension
tetracycline, ●​ Photosensitivity:
vancomycin ○​ Triamterene may cause →
■​ Ethacrynic acid: avoid excessive sun exposure
■​ Incompatible ●​ Patients should report:
with solutions ○​ Muscle pain, weakness,
with pH < 5 cramps
■​ Do not mix ○​ Nausea, vomiting, diarrhea
with whole ○​ Palpitations
blood ○​ Sudden joint pain (possible
■​ Furosemide: gout)
■​ May
precipitate
with ascorbic
acid, Use in Pregnancy
epinephrine,
norepinephrin ●​ Safety not fully established
e, tetracycline ●​ Routine use during pregnancy is not
indicated
●​ Not useful for toxemia
●​ May be used only if clearly needed
Patient Administration and Monitoring (e.g., CHF, renal disease)
●​ Crosses the placental barrier and
●​ Diuretics are fast-acting → take early may affect the fetus
in the day to avoid nocturia ●​ Use only if benefits outweigh risks
●​ Patients should:
○​ Take medication as
prescribed even if
asymptomatic
○​ Monitor body weight regularly
(daily in some cases)
○​ Take oral diuretics with meals
or milk if GI upset occurs
●​ Avoid alcohol:
○​ Potentiates ADH inhibition →
worsens dehydration,
dizziness, drowsiness
●​ Diabetes patients:
○​ Monitor blood glucose
○​ Inform all healthcare
providers of diuretic use
●​ Older adults:
○​ No special dose adjustment
usually required