PHA6118: Cardiovascular Physiology and Diuretics

Function of Cardiovascular System

to transport oxygen, nutrients, hormones, and waste products all throughout the body

Heart

a muscular organ that pumps blood throughout the body

Blood vessels

arteries, veins, and capillaries have different purposes but mainly for oxygen transport and nutrient/waste product exchange

Blood

liquid in the vessels carrying the oxygen to and carbon dioxide from the the body tissue

atria

upper chambers of the heart

ventricles

lower chambers of the heart

Pulmonary and Systemic circulation

It pumps blood throughout the body via two circulatory loops:

neurohormonal regulation

The cardiovascular physiology is under _ under the ANS

Heart rate, contractility, and vascular tone are various functions in the ANS

Sympathetic and Parasympathetic stimulation or blocking will have major effects in the cardiovascular physiology:

epinephrine and norepinephrine

What hormones affect the heart rate and vasoconstriction

𝛽-blockers

Decreases heart and cardiac contractility • Decreases cardiac workload and blood pressure

Ca-Channel blockers (CCBs)

Dilates blood vessels to lower pressure • Reduces heart rate by inhibiting Ca-influx into the cardiac smooth muscle

ACE Inhibitors / Angiotensin Receptor Blockers

Promotes vasodilation by blocking the RAAS leading reduced pressure

Diuretics

Increases urine output to lower blood volume and blood pressure

Antiplatelets and Anticoagulants

Prevents blood clot formation to lower risk of thrombosis and stroke

Diuretics

Drugs that increase urine volume by inhibiting the reabsorption of certain solutes (Na+ , K+ , Cl-) and/or water in the tubular system of the kidneys

nephron

is the functional unit of the kidney.

Renal Corpuscle

includes the Bowman’s Capsule and Glomerulus

Loop of Henle

includes the descending limb and ascending limb

Proximal Convoluted Tubules

Carries out isosmotic reabsorption of amino acids, glucose, numerous ions

Proximal Convoluted Tubules

Major site for NaCl and NaHCO3 reabsorption

Na+

In the PCT, it is separately absorbed from the lumen in exchange for H+ ions via NHE3 and is transported to the blood using the Na+/K+ ATPase (Na/K pump)

Sodium/hydrogen exchanger 3 (NHE3)

What transporter is used for the separate absorption of Na+ in the PCT

Carbonic anhydrase

enzyme required for the HCO3 - reabsorption process in the brush border and in the cytoplasm

Weak acid

absorption occurs at the early straight segment (S1) of PCT

Weak bases

are absorbed in the S1 and middle segment (S2).

SGLT2

Glucose is reabsorbed in PCT via _

Thick Ascending Limb

Pumps Na+/K+/Cl- out of the lumen and into the kidney interstitium via Na+/K+/Clcarrier (NKCC2 or NK2Cl)

Thick Ascending Limb

it is the major site for Ca+2/Mg+2 reabsorption which then creates a (+)- potential that is the driving force for the cation reabsorption.

Distal Convoluted Tubules

Actively pumps Na+/Cl- out of the lumen of the nephron via Na+/Clcarrier (NCC).

Na+/Cl carrier (NCC)

It is the transporter used for the active pumping of Na+/Cl-

Ca+2

_ is also reabsorbed in the DCT under the regulation of the parathyroid hormone (PTH).

Cortical Collecting Tubules

The last segment of Na+ reabsorption and is regulated by aldosterone.

epithelial sodium channel (ENaC)

In the Cortical Collecting Tubules, Na+ reabsorption is made via the _. This absorption is accompanied by K+/H+ excretion

Cortical Collecting Tubules

Primary site for urine acidification

ADH

activates V2 receptors (G-protein coupled) which stimulates levels of cAMP

cAMP

activates protein kinase A (PKA) that activates in turn aquaphorin-2 (AQP2) in the apical membrane of the collecting ducts’ cells.

Carbonic Anhydrase Inhibitors

MOA: Inhibition of carbonic anhydrase in the brush border and cytoplasm

Carbonic Anhydrase Inhibitors

Effects:

Leads to HCO3 - diuresis since HCO3 - is poorly absorbed leading to metabolic acidosis

Carbonic Anhydrase Inhibitors

Effects:
Reduced aqueous humor and cerebrospinal fluid production

Carbonic Anhydrase Inhibitors

Effects:
Significant K+ wasting when excess Na+ is reabsorbed.

Carbonic Anhydrase Inhibitors

Contraindicated for patients with hepatic encephalophathy due to possible hyperammonemia upon urinary alkalinization.

Carbonic Anhydrase Inhibitors

Acetazolamide

Brinzolamide

Dorzolamide

Methazolamide

Dichlorphenamide

Acetazolomide

protoype agent of Carbonic Anhydrase Inhibitors

Brinzolamide Dorzolamide

Helps in Glaucoma

Topical agents inhibits carbonic anhydrase locally and are good in preventing the needed HCO3 - supply without renal effects.

Acetazolamide

Help in urinary alkalization (crystinuria)

_ increase urine pH from 7.0-7.5 allowing better solubility for uric acid and cystine.

Must be monitored since effects of _ might be prolonged which may lead to unnecessary Ca-stone formation

Acetazolamide

helps in metabolic alkalosis

can rapidly correct the alkalosis and even provide diuretic effect to lower volume overload.

Acetazolamide

helps in Acute Mountain Sickness

Only in serious cases where pulmonary and cerebral edema is present, _ can reduced CSF formation and pH leading to increased ventilation

Carbonic Anhydrase Inhibitors

Adverse Effects

Hypochloremic Metabolic Acidosis

Phosphate and Calcium Renal Stones

Renal Potassium Wasting

Drowsiness and Parasthesias

Nervous System toxicity

Hypersensitivity

Drowsiness and Parasthesias

what happens if there is a high dose of Acetazolamide

Nervous System toxicity

it is an accumulated effect in the adverse effects of Carbonic Anhydrase Inhibitors

Hypersensitivity

In the adverse effects of carbonic anhydrase inhibitors, it is due to sulfonamide nature

Loop Diuretics

MOA: Inhibits the cotransport of Na+ , K+ , and Cl- via NKCC2 or NK2Cl.

Loop Diuretics

Most efficacious diuretic agents, rapidly absorbed and eliminated by glomerular filtration and tubular secretion

Loop Diuretics

Short-acting with action lasting within a 4-hour span

Loop Diuretics

Also known to interact with NSAIDs or Probenecid leading to decreased secretion of loop diuretics

Thiazide & Loop Diuretics

Contraindicated for patients with hepatic cirrhosis, borderline renal failure, and heart failure.

Loop Diuretics

Effects:

Leads to massive NaCl diuresis, blood volume reduction, and rapid excretion of edema fluid when tissue perfusion is adequate.

Loop Diuretics

Effects:

Reduction in the “diluting ability” of the nephron via the LOH which is the site of urinary dilution

Loop Diuretics

Effects:

Loss of positive-lumen potential that leads to:

• Reduced reabsorption of Ca+2 and Mg+2 cations.

• Significant increase in Ca+2 excretion

Loop Diuretics

Effects:

Induces expression of COX-2 for prostaglandin synthesis.

• PGE2 inhibits salt transfer in the TAL supporting the action of Loop diuretics.

• PG-mediated increase in blood flow through the vascular beds.

Loop Diuretics

Effects:

Potassium wasting leading to hypokalemic alkalosis

Loop Diuretics

Effects:

Reduction of pulmonary vascular pressure (MOA is unknown).

Loop Diuretics

Furosemide

Bumetanide

Torsemide

Ethacrynic acid

Furosemide

prototype; DOA is 2-3 hours; sulfonamide derivative

Furosemide, Bumetanide, Torsemide

sulfonamide derivative

Torsemide

DOA is 4-6 hours; sulfonamide derivative

Ethacrynic acid

– phenoxyacetic acid derivative

Loop Diuretics

The most important application is for edematous state (e.g., heart failure, acute pulmonary edema, ascites), hypertension and hypercalcemia.

Loop Diuretics

helps in Hyperkalemia

significantly enhances urinary excretion of K+ which is further enhance by NaCl and H2O co-administration.

Loop Diuretics

used for Acute Renal Failure

can increase rate of urine flow and urinary excretion of K+.

Loop Diuretics

helps with anion overdose

with co-administration of saline solution can treat toxic ingestion of Bromide, Chloride, and Fluoride.

Saline solution provides Na+/Cl- replacements and prevents extracellular volume depletion.

Loop Diuretics

Adverse Effects

Hypokalemic metabolic alkalosis secondary to potassiumwasting

Hypovolemia and CV complications

Hyperuricemia and Hypomagnesemia

Ototoxicity

Hypersensitivity due to sulfonamide origin of some members

Thiazide Diuretics

MOA: Inhibits NaCl transport in the early segment of DCT via NCC.

Thiazide Diuretics

Active via oral route and have longer DOA (6 to 12 hours) than Loop agents

Thiazide Diuretics

All are secreted by organic acid secretory system in the PCT and compete with uric acid (may elevate uric acid levels)

Thiazide Diuretics

When used with a loop agent, results to a synergistic effect leading to marked diuresis among patients

Thiazide and Loop Diuretics

Contraindicated for patients with hepatic cirrhosis, borderline renal failure, and heart failure

Thiazide Diuretics

Effects:

In full doses, produces moderate but sustained Na+/Cl- diuresis which may lead to hypokalemic metabolic alkalosis.

Thiazide Diuretics

Effects:

Reduction of intracellular Na+ and promotes Na+/Ca+2 exchange at the basolateral membrane – increased Ca+2 reabsorption; decreased urinary excretion of Ca+2

Thiazide Diuretics

Effects:
May reduce water excretion that may cause dilution hyponatremia

Thiazide Diuretics

Effects:

Reduction in blood pressure at lower doses than maximal diuretic doses

Thiazide Diuretics

Effects:

Reduced thiazide efficacy in cases of inhibited renal prostaglandin synthesis

Thiazide Diuretics

Hydrochlorothiazide

Chlorothiazide

Metolazone

Chlorthalidone

Indapamide

Hydrochlorothiazide

prototype of thiazide diuretics; sulfonamide derivative

Chlorothiazide

only member available for parenteral administration

Metolazone

combined with Loop for synergistic effects

Chlorthalidone

slowly absorbed, longer DOA

Indapamide

excreted by the biliary system; sufficiently cleared by the kidneys

Thiazide Diuretics

used in Hypertension

Despite mild effects during mono therapy, their inexpensive prices leads to better compliance comparable to the use of ACEi or CCBs.

Thiazide Diuretics

used for Edematous states

May be used in combination combination with Loop diuretics (first- choice) during severe salt and water retention.

Thiazide Diuretics

used for Nephrolithiasis

can reduce urinary Ca+2 concentration by promoting Ca+2 reabsorption in the DCT.

Thiazide Diuretics

used for Nephrogenic Diabetes Insipidus

Nephrogenic Diabetes insipidus results from inadequate response to ADH. _ can reduce polydipsia and polyuria associated with it.

Thiazide Diuretics

Adverse Effects

Hypokalemic metabolic alkalosis secondary to potassiumwasting

Hyponatremia

Hyperglycemia – high HCTZ dose leads to decreased insulin

Hyperlipidemia – 5-15% increase in LDL and cholesterol

Hyperuricemia

Weakness, fatigue, paresthesia, impotence

Hypersensitivity due to sulfonamide nature

Potassium-Sparing Diuretics

MOA:

Acts as pharmacologic antagonist of aldosterone in the collecting tubule

Potassium-Sparing Diuretics

MOA:

Inhibits epithelial sodium ion channel (ENaC)

Potassium-Sparing Diuretics

Effects:

Increases Na+ clearance and decreases K+/H+ ion excretion, hence the name “_”

Potassium-Sparing Diuretics

Contraindicated for patients with hyperkalemia (can be fatal), and liver disease.

Aldosterone antagonist

Spironolactone

Eplerenone

Finerenone