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Diuretics

• Diuretics are drugs that affect kidney function and promote increased water excretion.

Nephron Structure

• The nephron consists of the glomerulus, proximal tubule, Loop of Henle, and distal tubule.

Nephron Function

• Nephrons have three key functions.

Reabsorption

• Reabsorption of sodium, chloride, bicarbonate, potassium, and water occurs in the proximal convoluted tubule.
• The descending limb of the Loop of Henle is freely permeable to water.
• Additional sodium is reabsorbed in the ascending limb of the Loop of Henle.
• In the early distal convoluted tubule, additional sodium and chloride are reabsorbed, followed by water.
• Late distal convoluted tubule exchanges sodium for potassium, which is regulated by aldosterone.
• The final urine concentration is regulated by ADH in the late distal convoluted tubule.

How Diuretics Work

• Diuretics work by blocking sodium and chloride reabsorption.
• Blocking sodium and chloride reabsorption results in increased water excretion.
• Adverse impacts occur on extracellular fluid.
• Diuretics interfere with normal kidney function.
• Diuretics can commonly cause hypovolemia, acid-base imbalance, and electrolyte abnormalities.

Classifications of Diuretics

• The classifications of diuretics include loop diuretics, thiazide diuretics, osmotic diuretics, and potassium-sparing diuretics.

Loop Diuretics

• The prototype loop diuretic drug is Furosemide.
• The generic name is Furosemide.
• Its trade name is Lasix.
• Furosemide acts on the ascending Loop of Henle.
• Furosemide works by blocking sodium and chloride reabsorption.
• Furosemide prevents passive water reabsorption.
• Diuresis with furosemide is less dependent on kidney function.
• Furosemide can promote diuresis, even in patients with severe renal impairment.
• It is used to treat pulmonary edema associated with CHF, CHF, and edema.
• Furosermide is also used to treat hypertension not controlled by other diuretics.
• Furosemide is administered via oral, IV, or IM routes.

Thiazide Diuretics

• The prototype drug is Hydrochlorothiazide.
• One generic name is Hydrochlorothiazide.
• Microzide is one trade name.
• Acts on the early segment of the distal convoluted tubule.
• Hydrochlorothiazide inhibits sodium reabsorption, which results in increased secretion of sodium and water.
• Diuresis is dependent on kidney function.
• Hydrochlorothiazide will be less effective in patients with a GFR of less than 20 mL/min.
• The drug is used for essential HTN and edema related to.
• Adverse effects are dehydration, hypokalemia, and hypote.

Potassium-Sparing Diuretics

• The prototype drug is Spironolactone.
• One generic name is Spironolactone.
• One trade name is Aldactone.
• Spironolactone acts by blocking the action of aldosterone in the distal nephron.
• Aldosterone normally facilitates the exchange of sodium for potassium, leading to potassium excretion.
• Aldosterone inhibition retains potassium.
• Spironolactone aids in sodium excretion.
• This diuretic is used for HTN, edema, and CHF.
• Adverse effects are hyperkalemia and endocrine effects.

Osmotic Diuretics

• Mannitol is the prototype drug.
• The generic name is Mannitol.
• The trade name is Osmitrol.
• Mannitol acts through osmotic force and inhibits passive reabsorption of water.
• This class is used to reduce intracranial pressure.
• Osmotic diuretics are also used to reduce intraocular pressure.
• Potential adverse effects are edema, precipitation of CHF, and pulmonary.

Hemodynamics

• Hemodynamics is the study of blood flow and the forces involved in circulation.

Overview of the Circulatory System

• Blood flows from the right atrium through the body.
• Pressure decreases as the blood flows away from the heart.

Cardiac Output

• Cardiac output is determined by heart rate multiplied by stroke volume.
  • Cardiac Output = Heart Rate x Stroke Volume

Cardiac Output Explained

• Average cardiac output is 5L/minute.
• Factors affecting cardiac output are heart rate and stroke volume.

Heart Rate Explained

• Heart rate is primarily controlled by the autonomic nervous system.
• Normal heart rate is 60 – 100 bpm.

Stroke Volume Explained

• Stroke volume is the volume of blood expelled from the left ventricle during systole.
• Stroke volume is determined by myocardial contractility, cardiac afterload, and cardiac preload.
  • Cardiac afterload occurs after the heart.
  • Cardiac preload occurs before the heart.
• Normal stroke volume is 60 - 100mL.

Hemodynamics: Starling's Law

• When fiber length (ventricular diameter) increases, contractile force (stroke volume) increases.

Arterial Pressure Regulation

• Arterial Pressure = Peripheral Resistance x Cardiac Output
  • Peripheral Resistance is regulated primarily by vasodilation and vasoconstriction (arterioles).
• Arterial Pressure is regulated by 3 systems:
  • Autonomic Nervous System
  • Steady-state sympathetic tone
  • Baroreceptor reflexes
  • Renin-Angiotensin-Aldosterone System (RAAS)
  • Constriction of arterioles and veins
  • Retention of water in the kidneys
  • Kidneys
  • Natriuretic Peptides - released during volume overload

The Basics of the Renin-Angiotensin-Aldosterone System (RAAS)

• Renin is released by the when blood pressure is low.
• Renin converts angiotensinogen into angiotensin I.
• Angiotensin I is converted into angiotensin II by the angiotensin-converting enzyme (aka ACE).
• Angiotensin II narrows the blood vessels to raise BP.
• Angiotensin II stimulates the release of aldosterone from the adrenal glands.
• Aldosterone triggers sodium and water retention in the kidneys.
  • This increases blood volume, which in turn increases blood pressure

Anatomy and Physiology Notes on RAAS:

• Renin converts Angiotensinogen to Angiotensin I.
• Angiotensin-Converting Enzyme (ACE or Kinase II) converts Angiotensin I to Angiotensin II.
• Formation of Angiotensin II is influenced by Renin and Angiotensin-Converting Enzyme.

Physiology of the RAAS

• Renin catalyzes angiotensin I from angiotensinogen, which is the rate-limiting step in angiotensin II formation.
• Renin release is stimulated by decreased BP, decreased Blood Volume, decreased plasma sodium content, increased renal perfusion pressures, and stimulation of beta1 adrenergic receptors in the juxtaglomerular cells.
• Renin release is suppressed by opposite factors, via a negative feedback loop

Actions of Angiotensin II

• Angiotensin II is a Vasoconstrictor.
• Angiotensin II stimulates release of aldosterone.
• Angiotensin II causes alteration of cardiac and vascular structure.

Actions of Aldosterone

• Aldosterone regulates BP and blood volume.
• Aldosterone can result in pathologic cardiovascular effects.

ANGIOSTENSIN II & ALDOSTERONE Explained

ANGIOTENSIN II

• Angiotensin II is a POWERFUL vasoconstrictor.
  • Acts directly on vascular smooth muscle
    • SNS to promote release of norepinephrine
    • Adrenal medulla to promote release of epinephrine
    • CNS to sympathetic outflow to blood vessels
• Angiotensin II can cause structural changes to the heart & blood vessels which can result in results in cardiac remodeling and hypertrophy, HTN, HF, MI and atherosclerosis

ALDOSTERONE

• Aldosterone regulates blood volume & blood pressure.
  • Acts on the distal tubules of the kidney to cause retention of Na+ and excretion of K+
• Aldosterone has Pathologic CV effects.
  • Promotes cardiac remodeling & fibrosis
  • Activate SNS and suppress uptea of NE in the heart which promotes dysrhythmias
  • Promotion of vascular fibrosis
  • Disruption of baroreceptor reflex®

Drugs Acting on the RAAS

• Angiotensin-Converting Enzyme Inhibitors (ACEIs)
• Angiotensin II Receptor Blockers (ARBS)
• Aldosterone Antagonists
• Direct Renin Inhibitors

Classes of Drugs Acting on RAAS

• The prototype ACE inhibitor is Captopril.
• The prototype Angiotensin II Receptor Blocker is Losartan.
• The prototype Aldosterone Antagonist is Eplerenone.
• The prototype Direct Renin Inhibitor is Aliskiren.

Common ACE Inhibitors include

• Captopril (PROTOTYPE)
• Enalapril
• Lisinopril
• Ramipril
• Benazepril
• Fosinopril
• Moexipril
• Perinodpril
• Quinapril
• Trandolapril

Mechanism of Action for ACE inhibitors

   -Levels of angiotensin II are reduced by inhibiting ACE
   -Levels of bradykinin are elevated Inhibition of kinase II (ACE)

• ACE inhibitors are used in the following scenarios -Hypertension -Heart Failure -Acute MI -Left Ventricular Dysfunction -Diabetic & nondiabetic nephropathy - Prevention of MI, stroke, and death in patients at high risk for CV events

Adverse effects of ACE inhibitors

• 1ST Dose Hypotension
  • Greatest risk in those with severe hypotension, on diuretics or who have Na+/volume depletion
  • Minimize by starting with lower doeses or temporarily stopping diuretics a few days before starting ACE inhibitors.
• Hyperkalemia
• *Renal Failure
• *Cough
• Angioedema

Drug to Drug interactions while using ACE inhibitors

• Diuretics - intensify first-dose hypotension
• Antihypertensives - can cause Additive effects when on multiple medications effecting Bp.
• Lithium - ACE Inhibitors may result in toxic accumulations of lithium
• Nonsteroidal AntiInflammatory Drugs - can effect Antihypertensive effects of ACE inhibtors.

Action of Prototype Drug Captopril in Relation to Other ACE Inhibitors

• Competitively inhibits angiotensin-converting enzyme
  • Results in decreased levels of angiotensin II
• It treats HTN, HF, left ventricular dysfunction after MI, and diabetic nephropathy.
• May cause acute kidney injury/renal failure, angioedema, cough, hyperkalemia, hematologic effects, and dermatologic reactions.

Angiotensin II Receptor Blockers (ARBs)

• Losartan is the prototype.
• Other common ARBs include: -Valsartan -Azilsartan -Candesartan -Eprosartan -Irbesartan -Olmesartan -Telmisartan

Angiotensin II Receptor Blockers (ARBs): Mechanism of Action

• Blocks angiotensin II from activating its receptors in blood vessels, adrenal glands, and other tissues
• Dilates arterioles and veins
• Prevents pathologic cardiac structure changes
• Decreases release of aldosterone and excretion.
• Does NOT inhibit ACE (Kinase II)
• ARBs should not increase levels of bradykinin in the lung and should not have adverse effects of the lung.
• ARBs are prescribed for conditions such as hypertension, heart failure, myocardial infarction (MI), stroke prevention, diabetic nephropathy, and for patients unable to tolerate ACE inhibitors.

ARBs can have the following Adverse effects

• Renal Failure
• Risk of severe renal insufficiency in those with bilateral artery stenosis
• Cough :
• Low incidence of cough Angioedema - very rare
• Fetal Injury: Black Box Warning
  • Black Box Warning

Losartan facts

• Selective and competitive blockade of angiotensin II
• Treats HTN, stroke prevention, and diabetic nephropathy Potential Side effects include - Acute kidney injury/renal failure, hyperkalemia, angioedema, and cough

ALDOSTERONE ANTAGONIST

• Prototype Drug: Eplerenone Mechanism of Action: Selective blockade of aldosterone receptors
• Treats is Hpertension (HTN) and heart failure (HF
• Key adverside effect is Hyperkalemia
• Drug Interactions - Inhibitors of CYP3A4 and increase levels of eplerenone

DIRECT RENIN INHIBITORS

• Aliskiren is the prototype drug.
• This drug binds tightly to renin to inhibit cleavage of angiotensinogen to angiotensin I Aliskiren treats hypertension (HTN).
• You should also be aware of the following potential side effects - Hyperkalemia, diarrhea, cough, angioedema
• There is a Black Box Warning for potential Fetal Injury