Cardiovascular Drugs Notes (Diuretics, RAAS inhibitors, Adrenergic Drugs, CCBs)

Diuretics

Overview: Diuretics increase urine output by blocking Na⁺ and Cl⁻ reabsorption, thereby changing osmotic pressure within the nephron and promoting passive water loss.
Major classes:
- Loop (High Ceiling) diuretics
- Thiazide diuretics
- Potassium-sparing diuretics

Diuretics • How they work

The amount of diuresis is directly related to the amount of Na⁺ & Cl⁻ reabsorption blocked in the nephron.
Blocking Na⁺ & Cl⁻ reabsorption changes osmotic pressure in the nephron, promoting passive water reabsorption? (Diuresis).
Overall effect: increased excretion of Na⁺, Cl⁻, and water; reduced extracellular fluids.

Osmolality and nephron sites (key diuretic targets)

Peritubular fluid osmolality: $300\ ext{mOsm/L}$
Mannitol (osmotic diuretic) acts in the proximal tubule.
Proximal convoluted tubule: NaCl reabsorption ~ $65\%$ of filtered Na⁺/Cl⁻
Thick ascending limb (loop): Na⁺ reabsorption targeted by loop diuretics (~ $20\%$ of Na⁺ reabsorption)
Early distal convoluted tubule: Na⁺/Cl⁻ reabsorption targeted by thiazides (~ $10\%$ )
Distal nephron (late distal convoluted tubule and collecting duct): K⁺-sparing diuretics act here; overall small contribution to diuresis
Medulla and cortex osmolality gradients: medullary gradient ↑ to $1200\ \mathrm{mOsm/L}$ ; corticomedullary gradient important for concentrating/diluting urine
General action: loop diuretics act on the thick ascending limb; thiazides on the early distal tubule; K⁺-sparing diuretics on late distal tubule/collecting duct.

Nephron sites of action (diuretic classes)

Proximal straight tubule – Carbonic anhydrase inhibitors (not detailed above but part of diuretic family)
Proximal convoluted tubule – Osmotic diuretics (e.g., Mannitol)
Thick ascending limb – Loop diuretics
Early distal convoluted tubule – Thiazide diuretics
Late distal convoluted tubule & collecting duct – K⁺-sparing diuretics (spironolactone, triamterene)
Collecting duct – Final site for water reabsorption and Na⁺ exchange under hormonal control

Loop/High Ceiling diuretics

Act in the ascending limb of the loop of Henle to block Na⁺/K⁺/2Cl⁻ cotransport.
Produce profound diuresis; can still be effective when GFR is low.
Potent but with notable adverse effects.
PO onset: within $60\ \text{min}$ ; duration of action ≈ $8\ \text{hours}$ .
Common adverse effects: hypovolemia, electrolyte disturbances, dehydration, hypotension, ototoxicity (especially with loop diuretics), hyperglycemia, hyperuricemia.
Ototoxicity: Furosemide (Lasix) – transient hearing loss; Ethacrynic acid – irreversible hearing loss.

Thiazide diuretics

Act in the early distal convoluted tubule to block Na⁺/Cl⁻ reabsorption.
Less diuresis than loops but useful in hypertension and edema.
PO onset: diuresis within $2\ \text{hours}$ ; peak effect in $4-6\ \text{hours}$ ; duration ≈ $12\ \text{hours}$ .
Require GFR > $15-20\ \,\text{mL/min}$ to be effective.

Potassium-sparing diuretics

Act in late distal convoluted tubule and collecting duct (distal nephron).
Modest diuresis; also promote Na⁺ excretion with K⁺ retention.
Examples: spironolactone (aldosterone antagonism) and triamterene (direct Na⁺-K⁺ exchange blockade).
Spironolactone: steroid derivative; blocks aldosterone in distal nephron; reduces Na⁺ reabsorption and K⁺ excretion.
Triamterene: directly inhibits Na⁺-K⁺ exchange mechanism; maintains K⁺ while promoting Na⁺ excretion.
In combination with thiazides, diuretic effect can be enhanced while mitigating K⁺ loss (e.g., Dyazide, Maxzide).

Diuretics – Adverse effects (summary)

Electrolyte imbalances: hyponatremia, hypochloremia, hypokalemia (more with loops and thiazides), hyperkalemia with K⁺-sparing diuretics.
Dehydration and hypotension due to extracellular fluid loss.
Ototoxicity: primarily with loop diuretics (furosemide, ethacrynic acid).
Hyperglycemia: uncommon with furosemide; may involve inhibition of insulin release, increased glycogenolysis, or decreased glycogen synthesis.
Hyperuricemia: can precipitate gout; especially with loop diuretics and thiazides.
Lipid effects: ↓ HDL; ↑ LDL and triglycerides observed with some diuretics.
Drug interactions:
- Digoxin: ↓ K⁺ (risk of digoxin toxicity with hypokalemia); monitor K⁺ and digoxin levels; may require K⁺ supplementation.
- Lithium: ↓ Na⁺ → ↓ Li⁺ excretion; monitor Na⁺ and Li⁺ levels; adjust lithium dose PRN.
- NSAIDs: ↓ diuretic effect by inhibiting renal prostaglandin synthesis → reduced renal perfusion; monitor.
- Other considerations: ototoxic drugs (loops) + K⁺ sparing diuretics effects; interactions with antihypertensives.
Pregnancy/breastfeeding: diuretics not used unless absolutely necessary.

Diuretics – Special notes

Electrolyte disturbances: Na⁺, Cl⁻, K⁺, Mg²⁺, Ca²⁺ can be reduced; uric acid may rise.
Dehydration can predispose to thrombosis/embolism.
Hypotension and volume loss contribute to symptoms.
K sparing diuretics reduce K⁺ loss but risk hyperkalemia; use with caution in CKD and with ACE inhibitors/ARBs.

K sparing specifics

Spironolactone
- Mechanism: Aldosterone receptor antagonist in the distal nephron; blocks Na⁺ reabsorption and K⁺ excretion, leading to K⁺ retention.
- Adverse effects: Hyperkalemia; endocrine effects including gynecomastia, menstrual irregularities, impotence, hirsutism, voice changes.
Triamterene (Dyrenium)
- Mechanism: Direct inhibition of the Na⁺-K⁺ exchange mechanism in the distal nephron; Na⁺ excretion increased; K⁺ retained.
- Adverse effects: Hyperkalemia; nausea & vomiting; leg cramps; dizziness.
Combinations:
- Triamterene combined with hydrochlorothiazide (HCTZ) in products such as Dyazide, Maxzide.

Unexpected use of hydrochlorothiazide

Diabetes insipidus: HCTZ can paradoxically reduce urinary output in some cases.

Angiotensin II inhibition

ACE Inhibitors & ARBs overview

ACE inhibitors block the conversion of angiotensin I to angiotensin II and also increase bradykinin levels by inhibiting its breakdown; ARBs block angiotensin II receptors rather than production.
The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure, blood volume, fluid and electrolyte balance.

RAAS system (key components and effects)

Liver produces angiotensinogen.
Lungs and renal endothelium produce ACE (angiotensin-converting enzyme).
Kidney juxtaglomerular apparatus releases renin in response to reduced renal perfusion; renin catalyzes angiotensin formation from angiotensinogen.
Angiotensin II causes arteriolar vasoconstriction (↑BP), stimulates aldosterone secretion (Na⁺ and water retention; K⁺ excretion), and can promote renal and vascular remodeling.
ADH (vasopressin) may be modulated by RAAS signaling; collecting duct reabsorbs water.
Bradykinin breakdown is inhibited by ACE inhibitors, contributing to vasodilation and adverse effects.

ACE Inhibitors

Mechanism: Inhibit angiotensin II production and increase bradykinin (vasodilation).
Effects: Vasodilation of arterioles; some venodilation; decreased blood volume; can prevent or reverse remodeling of heart/vessels.
Adverse effects: First-dose hypotension; hyperkalemia; fetal injury; cough (from bradykinin); angioedema.
Advantages over other drugs: potential improvements in exercise capacity, reduced orthostatic hypotension, favorable effects on uric acid, glucose, and lipid profile; may have favorable effects on symptoms of fatigue and sexual function (text notes various arrows indicating direction of effects).
Benefits in disease states: heart failure (improved regional blood flow, ↑ cardiac output, reduced edema, natriuresis), acute MI (reduced mortality and progression to heart failure), nephropathy (slowed progression; reduced glomerular pressure).
Contraindications: Pregnancy (fetal injury in 2nd/3rd trimesters); renal artery stenosis (risk of renal failure).
Adverse effects summary: Angioedema, cough, hyperkalemia, allergic reactions (rash), impaired taste, neutropenia.

Angiotensin II receptor blockers (ARBs)

Mechanism: Angiotensin II receptor antagonists block AT1 receptors, preventing angiotensin II effects but without increasing bradykinin to the same extent as ACE inhibitors.
Effects: Similar indications as ACE inhibitors (HTN, HF); less effect on bradykinin-related side effects; may have less impact on K⁺ levels.
Adverse effects: Dizziness; rare angioedema; hyperkalemia (less than ACE inhibitors);
Advantages: Used when ACE inhibitors are not tolerated (e.g., cough or angioedema).
Contraindications: Pregnancy; renal artery stenosis.

Adrenergic Drugs

β₁ agonists

Activation of β₁ receptors in the heart has clinical significance; activation in kidneys has minimal clinical significance here.

β₁ antagonists (beta-blockers)

Block β₁ receptors in the heart: ↓ heart rate, ↓ force of contraction, ↓ velocity of AV conduction.
Commonly used for: hypertension, angina, dysrhythmias, MI, cardiac symptoms of hyperthyroidism, migraine, glaucoma.
Adverse effects: Bradycardia; decreased cardiac output leading to heart failure; AV block; bronchoconstriction (β₂ related, more with nonselective agents); inhibition of glycogenolysis (hypoglycemia awareness reduced).
Additional adverse effects: can mask signs of hypoglycemia; may cause exercise intolerance; CNS effects (depression, insomnia, nightmares, hallucinations).
Drug examples: selective β₁ blockers (e.g., metoprolol) and nonselective β blockers (e.g., propranolol).

Calcium Channel Blockers (CCBs)

General mechanisms

Effects on the heart:
- Myocardium: block Ca²⁺ channels → ↓ contractile force.
- SA and AV nodes: Ca²⁺-regulated; blocking Ca²⁺ channels → ↓ heart rate and ↓ AV conduction velocity.
Direct effects on vascular smooth muscle (VSM): blockade of Ca²⁺ channels → vasodilation and ↓ arterial pressure; improved coronary perfusion.
Direct effects on myocardium: ↓ force of contraction when applicable.
Indirect effects: reduced BP can trigger baroreceptor reflexes that increase sympathetic activity to the heart (norepinephrine release → ↑ HR, ↑ AV conduction, ↑ contractile force) in some cases (rapid-acting dihydropyridine agents).
Net effect: decreased arterial pressure with potential changes in heart rate depending on the agent and rapidity of action; increased coronary perfusion.

Agents and their profiles

Verapamil and Diltiazem: used for angina, HTN, and certain dysrhythmias. Produce vasodilation, lower arterial pressure, and improve coronary perfusion.
Nifedipine: used for angina and HTN. Causes vasodilation and can produce reflex tachycardia; rapid-acting formulations can increase heart rate and contractility (reflex tachycardia).

Adverse effects (common to all CCBs)

Flushing, headache, peripheral edema, gingival hyperplasia.

Adverse effects by agent

Verapamil / Diltiazem: dizziness; bradycardia; AV block; reduced contractility.
Nifedipine: reflex tachycardia; less constipation than verapamil/diltiazem but rapid-acting forms associated with adverse outcomes in MI/angina in some settings.

Interactions

Verapamil/Diltiazem with digoxin: ↑ risk of AV block; monitor digoxin levels.
-β blockers with Verapamil/Diltiazem: risk of excessive cardiac suppression.
Nifedipine with β blockers: can prevent reflex tachycardia.

Toxicity

Verapamil/Diltiazem toxicity: hypotension, bradycardia, AV block, ventricular tachyarrhythmias.
Nifedipine toxicity: excessive hypotension, bradycardia, AV block, ventricular tachyarrhythmias; note excessive dose selectivity loss leading to adverse effects.

Selecting an Appropriate Agent

Uncomplicated hypertension – monotherapy

Common initial options: Diuretics, ACE inhibitors/ARBs, CCBs.

Initial therapy in hypertension with comorbid conditions

Choose a drug appropriate for the comorbid condition; therapy should be individualized.

Lower morbidity & mortality with comorbid conditions (examples)

DM with proteinuria: Preferred drugs include ACE inhibitors; also beta blockers, ARBs, and diuretics.
Heart failure: ACE inhibitors, beta blockers, diuretics, CCBs; in some cases ACE inhibitors help reduce mortality and edema.
Isolated systolic hypertension, MI without systolic dysfunction, MI with systolic dysfunction: ACE inhibitors, beta blockers, diuretics, CCBs as appropriate.
Preferred drug combinations: often ACE inhibitors or ARBs with diuretics or CCBs; in some cases beta blockers preferred.

Favorable effects for specific comorbid conditions

Angina, atrial tachycardia & atrial fibrillation; DM with proteinuria; type 1 & 2 DM with proteinuria; dyslipidemia: beta blockers, CCBs, ACE inhibitors; low-dose diuretics; alpha blockers as applicable.

Multidrug therapy

Must come from different drug classes to maximize effectiveness and minimize adverse effects.
Advantages: increased effectiveness, allows for lower doses of each drug, reduces adverse effects overall.

Special considerations for the elderly

Avoid drugs that cause orthostatic hypotension if possible.
Avoid central acting alpha blockers due to potential cognitive dysfunction.

Summary and practical implications

Diuretics remain foundational for many HTN patients and edema; choice depends on GFR, electrolyte profile, and comorbidities.
RAAS inhibitors (ACE inhibitors and ARBs) provide organ-protective effects in the heart and kidneys, with notable bradykinin-related adverse effects for ACE inhibitors.
Beta-blockers are versatile for cardiovascular and some non-cardiovascular conditions but require caution in COPD/Asthma (nonselective agents) and in diabetics.
Calcium channel blockers offer versatile control of BP and angina; selection depends on patient tolerance to edema, constipation (verapamil), and reflex tachycardia (nifedipine).
Individualized therapy, attention to comorbidities (DM, heart failure, post-MI, pregnancy) and potential drug interactions is essential for optimizing outcomes.

Discussion

Review scenarios for choosing an antihypertensive regimen based on comorbidity, patient age, and risk factors.
Consideration of adverse effect profiles and monitoring parameters (BP, electrolytes, renal function, digoxin/Lithium levels where applicable).