Pharmacology: Pharmacokinetics, Pharmacodynamics, and Renal Drug Handling (Diuretics & Kidney Function)

Pharmacokinetics and Drug Interactions (Pharmacokinetic vs Pharmacodynamic)

• Key distinction: pharmacokinetic drug interactions change the levels of a drug in the plasma by altering absorption, distribution, metabolism, or excretion; pharmacodynamic interactions change the effect of drugs without changing their plasma levels.

• Enzyme inhibition vs enzyme induction (pharmacokinetic):

  • Enzyme inhibition decreases metabolism of a drug, leading to higher active drug levels and potential toxicity.

  • Enzyme induction increases metabolism, lowering active drug levels and potentially reducing efficacy.

• Prodrugs vs active drugs (pharmacokinetics):

  • Prodrug: an inactive compound that must be metabolized to an active drug in the body.

  • Most common site of metabolism: the liver.

  • Consider how enzyme inhibition or induction affects four scenarios:

  • Active drug + enzyme inhibition → higher active drug levels (risk of toxicity)

  • Active drug + enzyme induction → lower active drug levels (risk of lack of efficacy)

  • Prodrug + enzyme inhibition → more prodrug (less active drug) because activation is slowed

  • Prodrug + enzyme induction → more active drug (faster activation)

• Practical exam tip: be able to map the four scenarios (active vs prodrug with inhibition vs induction) and predict whether active drug levels go up or down, or whether there is toxicity or lack of effect.

• Pharmacodynamic drug interactions (no change in drug levels):

  • Antagonistic interactions: one drug reduces the effect of another (offsetting effects).

  • Additive effects: the combined effect equals the sum of individual effects.

  • Synergistic effects: combined effect exceeds the sum of individual effects (1 + 1 could be 2, 3, or more).

  • Examples:

  • Antagonistic PD interaction: one drug lowers blood pressure while another raises it, offsetting benefits.

  • Synergistic PD interaction: two drugs both lower blood pressure, producing a larger drop when used together.

  • Synergistic adverse PD interaction: CNS depressants or anticholinergic effects that, when combined, produce excessive sedation or anticholinergic side effects.

• CNS depressants and anticholinergic effects: combining CNS depressants or anticholinergic agents can amplify side effects (e.g., dry mouth, urinary retention, constipation, drowsiness).

• Herbals and drug interactions: increasing use of nonprescription/herbal products can cause serious interactions, especially with anticoagulants, antiplatelets, or antidepressants.

  • Examples mentioned: Ginseng and garlic affect coagulation; Ginkgo and ginger affect coagulation; Saint John’s wort can induce antidepressant effects and interact with SSRIs; Kava is a CNS depressant; These interactions emphasize taking a thorough medication history, including herbal supplements.

• Important clinical point: most drug–drug interactions are not inherently dangerous; they become dangerous if not recognized and managed (timing, dosing adjustments, monitoring).

Renal System: Structure, Function, and Drug Handling

• Primary importance: kidneys are essential for excreting drugs; many drugs are renally eliminated, so renal function directly affects drug levels and dosing.

• Major roles:

  • Maintain fluid and electrolyte balance

  • Eliminate dissolved metabolic wastes and excess water/electrolytes

  • Handle many drugs that require renal elimination

• Anatomy (brief):

  • Kidneys — site of filtration and reabsorption; nephron as functional unit

  • Ureters — transport urine to the bladder

  • Bladder — stores urine

  • Urethra — exit pathway for urine

• Nephron components and flows:

  • Afferent arteriole carries blood into the glomerulus; efferent arteriole carries blood away from the glomerulus.

  • Glomerulus: site of glomerular filtration; filtration results in the movement of fluid and dissolved substances from blood into the tubular system.

  • Tubule: site of reabsorption and secretion; major segments include proximal tubule, loop of Henle (descending and ascending limbs), distal tubule, collecting duct.

  • Collecting ducts drain into the ureter and bladder.

• Glomerular filtration rate (GFR): the rate at which fluid moves from the blood into the renal tubules; critical for kidney function assessment.

• Glomerular filtration: governed by pressure; the efferent arteriole is constricted to raise glomerular pressure, promoting filtration into the tubules.

• Tubular reabsorption: movement from the tubular lumen back into the blood

  • Proximal tubule: ~60–70% of water and sodium reabsorbed early

  • Descending limb of the loop of Henle: limited sodium permeability; less water reabsorption

  • Ascending limb of the loop of Henle: high sodium permeability; fine-tunes reabsorption

  • Distal tubule: remaining ~5–10% reabsorbed; final tuning occurs here

  • Collecting duct: final regulation; aldosterone and ADH modulate water/sodium handling

• Tubular secretion: movement from blood into the tubular lumen for excretion

• Aldosterone and ADH (antidiuretic hormone): key hormonal regulators of final urine composition

  • Aldosterone: promotes sodium reabsorption in the distal tubule; indirectly promotes water reabsorption; increases blood volume

  • ADH (vasopressin): promotes water reabsorption in the collecting duct; anti-diuresis; prevents water loss when dehydrated

• Analogies to aid understanding:

  • “Diamonds in sand” analogy: Kidney dumps everything into the tubular system (the sand), then reclaims (reabsorbs) the exact things we want to keep (the diamonds: Na+, water, glucose, proteins) from the tubule back into the bloodstream; waste products (sand) are mostly excreted.

  • “Memory foam edema” analogy: edema pits reflect fluid that can be displaced with pressure; pitting edema indicates interstitial fluid accumulation; severity judged by pit depth and how far up the leg edema extends.

Fluid Balance, Edema, and Related Conditions

• Types of edema and fluid redistribution:

  • Peripheral edema: fluid accumulation in interstitial space, often in legs

  • Pulmonary edema: fluid in the lungs; medical emergency; requires rapid management

  • Ascites: fluid accumulation in the abdominal cavity, common with liver disease; diaphragmatic pressure impairs breathing; management may include therapeutic tap but must address underlying cause

  • Lymphedema: impaired lymphatic return; can occur after lymph node removal/radiation; compression garments help return fluid to circulation

• Pathophysiology of edema relates to shifts in intravascular and interstitial fluid and the balance of forces (including oncotic pressure from albumin) that keep fluid in the vasculature.

• Clinical monitoring in edema management includes tracking signs of hypovolemia or dehydration when aggressive diuresis is used: blood pressure, orthostatic changes, daily weights, intake/output, and laboratory values (potassium, sodium, BUN, creatinine).

Diuretics: Classes, Mechanisms, Indications, and Side Effects

• Goal of diuretics: increase diuresis to reduce extracellular fluid volume; most work by interrupting sodium reabsorption, with water following via osmotic forces.

• General principle: where sodium goes, water follows. Block sodium reabsorption → less water reabsorbed → more urine output.

• Common diuretic categories and key points:

Thiazide diuretics

• Examples: hydrochlorothiazide (most common), chlorthalidone, metolazone, bend?; among these,indapamide/dapamide variants may appear

• Mechanism: inhibit sodium reabsorption in the distal tubule

• Degree of diuresis: relatively weak; targets early near the distal tubule; typically reduces about 10% of sodium reabsorption remaining after proximal/distal segments

• Ceiling effect: low ceiling; after a couple doses, further diuretic effect plateaus

• Limitations: less effective in patients with renal impairment

• Clinical note: commonly used for hypertension (BP-lowering effects beyond volume loss); not ideal for sustained edema management due to low ceiling and diminished efficacy in renal disease

Loop diuretics

• Examples: furosemide (Lasix), bumetanide, torsemide

• Mechanism: block sodium reabsorption in the loop of Henle; affect ~20–25% of sodium reabsorption

• Efficacy: most potent diuretics; can produce large diuresis and are not as dependent on renal function as thiazides; retain efficacy in renal disease

• Dose-response: infinite (high ceiling) dose response; can titrate doses upward for greater effect

• Routes: oral and intravenous (IV) forms; IV often used in hospitalized patients needing rapid and predictable action

• Indications: edema from heart failure, liver disease, kidney disease; can lower blood pressure primarily when edema is the cause of hypertension

• Side effects: hypokalemia, hypovolemia, orthostatic hypotension, hyperglycemia (glucose intolerance in diabetics), calcium wasting (hypocalcemia) and ototoxicity (hearing loss, tinnitus) with high-dose use

• Important pharmacokinetic note: loops are often the diuretic of choice in acute edema and congestive states due to robust effect

Potassium-sparing diuretics

• Examples: amiloride, triamterene

• Mechanism: block sodium channels in the distal tubule; weak diuretics on their own

• Effect on potassium: promote potassium retention (hyperkalemia risk)

• Clinical use: often used in combination with thiazides to balance potassium loss

Aldosterone antagonists (mineralocorticoid receptor antagonists)

• Examples: spironolactone, eplerenone

• Mechanism: antagonize aldosterone at aldosterone receptors (serious differentiation from potassium-sparing diuretics); block aldosterone-driven water/sodium retention

• Potassium: both cause potassium retention (hyperkalemia risk)

• Distinctions and uses:

  • Do not replace thiazides or loops; they are used in specific states with high aldosterone (e.g., heart failure, liver failure)

  • Spironolactone has hormonal side effects (gynecomastia in men, menstrual irregularities in women, hirsutism, potential erectile dysfunction) due to antiandrogen effects; also used for hormonally driven acne in some women

  • Eplerenone has fewer antiandrogenic effects but may still cause hyperkalemia

Osmotic diuretics

• Examples: glycerin, mannitol, urea

• Mechanism: filtered by the glomerulus and remain in the tubular lumen; they are not reabsorbed and thus pull water into the tubule (osmotic effect)

• Primarily used for: moving fluid from areas where it is problematic (e.g., cerebral edema, raised intracranial pressure, certain glaucoma situations) rather than routine diuresis

• Note: not outpatient diuretics; action is more about moving fluid than terminally increasing urine output for volume reduction

Carbonic anhydrase inhibitors

• Example: acetazolamide

• Mechanism: inhibit carbonic anhydrase; reduces aqueous humor production in glaucoma; modest diuretic effect; rarely used for diuresis

• Uses: glaucoma (primary use); certain drug overdoses to alter urine pH and facilitate excretion; not a first-line diuretic for edema

Other notes on diuretic use and combinations

• Thiazide and loop diuretics can have overlapping mechanisms, but loop diuretics provide stronger diuresis and retain effectiveness in renal disease; thiazides may be favored for mild edema or hypertension not primarily due to volume overload

• Combining diuretics can be used to enhance diuresis (synergistic therapeutic PD effect) and to balance adverse effects (e.g., combining thiazide with a potassium-sparing diuretic to prevent hypokalemia)

• Practical considerations:

  • Monitor for dehydration/hypovolemia and orthostatic hypotension

  • Monitor electrolytes, especially potassium; loop and thiazides tend to cause hypokalemia; potassium-sparing aldosterone antagonists raise potassium

  • Monitor glucose tolerance in diabetics; loop diuretics can worsen glucose tolerance in some patients

  • Monitor bone calcium with long-term diuretic use (risk of calcium wasting with loops)

  • Monitor ototoxic effects with loop diuretics, especially at high doses

Clinical Considerations and Monitoring During Diuretic Therapy

• Key monitoring parameters when using diuretics (especially in hospitalized patients):

  • Daily weights to track fluid shifts and objective edema reduction

  • Intake and output (in IS or mL) to assess net fluid balance

  • Blood pressure and orthostatic changes to detect hypovolemia and ensure cerebral perfusion

  • Labs: potassium, sodium, BUN, creatinine to monitor electrolyte balance and renal function

  • Hydration status: mucous membranes, skin turgor, mucosal moisture, capillary refill

  • Cardiac monitoring for arrhythmias if potassium disturbances occur

• Management strategies for adverse effects or events:

  • If hypokalemia occurs with loop/thiazide therapy, consider potassium supplementation or co-prescription of a potassium-sparing diuretic

  • If hyperkalemia occurs with aldosterone antagonists or potassium-sparing diuretics, adjust dose or discontinue

  • In patients at risk for hypovolemia (e.g., elderly, congestive heart failure patients), be cautious with diuretic dosing; avoid excessive rapid diuresis

• Special patient populations and considerations:

  • In older adults and those with chronic kidney disease, thiazides may be less effective; loops are more reliable for edema in these populations

  • In patients with significant kidney disease, monitor renal function and adjust diuretic therapy accordingly

  • Diuretic dosing may need to be adjusted in patients with comorbid conditions such as diabetes or osteoporosis due to metabolic effects

Renal Function Assessment for Drug Dosing: Creatinine Clearance and GFR

• Why we care: many drugs are renally eliminated; dosing must account for renal function to avoid toxicity

• Creatinine and creatinine clearance (CrCl):

  • Creatinine is produced at a fairly constant rate based on muscle mass and is eliminated primarily by glomerular filtration.

  • A proxy for GFR is CrCl, calculated using the Cockcroft–Gault formula (historically common). It is an estimate and has limitations across different populations.

  • Cockcroft–Gault (for men):
    {CrCl_{men}} = rac{(140 - ext{age}) imes ext{weight (kg)}}{ ext{serum creatinine (mg/dL)} imes 72}

  • For women, multiply by 0.85:
    $${CrCl_{women}} = 0.85 imes rac{(140

Here are 8 exam-based questions derived from the provided notes:

1. Multiple Choice: A patient is taking a drug that is primarily metabolized by a specific liver enzyme. If a new medication is added that inhibits this enzyme, what is the most likely pharmacokinetic outcome for the first drug?
   a. Lower active drug levels and potential lack of efficacy
   b. Higher active drug levels and potential toxicity
   c. Faster activation if the drug is a prodrug
   d. No change in active drug levels

2. Select All That Apply: Which of the following scenarios would lead to an increase in the active drug levels or a faster activation of the active drug?
   a. Active drug + enzyme inhibition
   b. Active drug + enzyme induction
   c. Prodrug + enzyme inhibition
   d. Prodrug + enzyme induction
   e. Synergistic pharmacodynamic effect

3. Matching: Match the nephron component with its primary function:
   (i) Glomerulus (A) Site of most reabsorption of water and sodium
   (ii) Proximal Tubule (B) Promotes water reabsorption in collecting duct
   (iii) Collecting Duct (C) Site of glomerular filtration
   (iv) ADH (D) Final regulation of water/sodium with hormones

   a. (i)-C, (ii)-A, (iii)-D, (iv)-B
   b. (i)-A, (ii)-C, (iii)-D, (iv)-B
   c. (i)-C, (ii)-A, (iii)-B, (iv)-D
   d. (i)-B, (ii)-A, (iii)-C, (iv)-D

4. Multiple Choice: A patient presents with fluid accumulation in the abdominal cavity, causing diaphragmatic pressure and impaired breathing. This condition is best described as:
   a. Peripheral edema
   b. Pulmonary edema
   c. Ascites
   d. Lymphedema

5. Matching: Match each diuretic class with its primary mechanism of action and location:
   (i) Thiazide diuretics (A) Block sodium reabsorption in loop of Henle
   (ii) Loop diuretics (B) Antagonize aldosterone at receptors
   (iii) Potassium-sparing diuretics (C) Block sodium channels in distal tubule
   (iv) Aldosterone antagonists (D) Inhibit sodium reabsorption in distal tubule

   a. (i)-C, (ii)-A, (iii)-D, (iv)-B
   b. (i)-D, (ii)-A, (iii)-C, (iv)-B
   c. (i)-A, (ii)-D, (iii)-C, (iv)-B
   d. (i)-D, (ii)-C, (iii)-A, (iv)-B

6. Select All That Apply: Which of the following are true characteristics or common side effects of loop diuretics?
   a. They are less effective in patients with renal impairment.
   b. They have a low ceiling effect and plateau after a couple of doses.
   c. They are the most potent diuretics and retain efficacy in renal disease.
   d. Common side effects include hypokalemia, hypovolemia, and ototoxicity.
   e. They promote potassium retention.

7. Multiple Choice: Which of the following statements about aldosterone antagonists (e.g., spironolactone, eplerenone) is correct?
   a. They primarily inhibit sodium reabsorption in the loop of Henle.
   b. They are commonly used as first-line diuretics for essential hypertension due to their strong diuretic effect.
   c. Spironolactone can cause hormonal side effects such as gynecomastia due to its antiandrogen effects.
   d. They cause potassium wasting and are often combined with loop diuretics to prevent hyperkalemia.

8. Select All That Apply: When monitoring a patient on diuretic therapy, which of the following parameters are crucial to track?
   a. Daily weights
   b. Intake and output
   c. Blood pressure and orthostatic changes
   d. Serum potassium, sodium, BUN, and creatinine levels
   e. Mucous membranes, skin turgor, and capillary refill for hydration status