PM 719 Pharmacology II Lecture Notes (LN) Chap 15 Diuretics PDF

PM 719 Pharmacology II Lecture Notes (LN) Chap 15 Diuretics Chapter 15 Diuretics DRUGS: **acetazolamide\* furosemide\* amiloride\* bumetanide\*** **brinzolamide ethacrynic acid\* triamterene\* chlorthalidone\*** **dapaglifozin hydrochlorothiazide\* mannitol\* glycerin\*** **canaglifozin spirono...

PM 719 Pharmacology II Lecture Notes (LN) Chap 15 Diuretics Chapter 15 Diuretics DRUGS: **acetazolamide\* furosemide\* amiloride\* bumetanide\*** **brinzolamide ethacrynic acid\* triamterene\* chlorthalidone\*** **dapaglifozin hydrochlorothiazide\* mannitol\* glycerin\*** **canaglifozin spironolactone\* conivaptan bumetanide** **caffeine eplerenone\* tolvaptan nesiritide** **\* Listed as a required drug in the AAPMC Curricular Guide 2023 edition, pg 115** TERMS: diuresis = increase urine volume diuretic = drug that increases urine volume reabsorption = the removal (taking back) of naturiuretic = increase in sodium (Na) excretion solutes and water into blood aquaretic = increase in excretion of solute-free water secretion = removal of solutes from solute = any dissolved ions, molecules etc. blood back into lumen PCT = proximal convoluted tubule diuresis = passage of large amounts TAL = thick ascending limb (of Henle) of urine DCT = distal convoluted tubule autacoid = bioactive substances SGLT = sodium-glucose cotransporter produced within the kidney NaHCO~3~ = sodium bicarbonate GFR = glomerular filtration rate GFR = glomerular filtration rate ADH = antidiuretic hormone filtration = movement of solutes and water from blood into the lumen NSAID = non-steroidal anti-inflammatory drug (aspirin etc.) The primary goal of this chapter to answer the following questions: MOA of diuretic drugs, where do they work in the nephron (what specific location), what ions are being Blocked or altered, and what pumps or transporters are involved. Brief Review of Renal Physiology: The kidney has three main functions: **filtration**, **reabsorption** and **secretion** (see above for definitions) **The following is a summary and overview of the diuretic chapter:** **[Drug Class Actions Location Example Drugs ]** Carbonic Anhydrase (CA) Inhibitors block reabsorption of NaHCO~3~ PCT **acetazolamide** SGLT Inhibitors inhibit Na/glucose transporter PCT **dapagliflozin** Loop Diuretics inhibit NaCl reabsorption TAL **furosemide** **ethacrynic acid** **bumetanide** **torsemide** Thiazide Diuretics inhibit NaCl reabsorption DCT **hydrochlorothiazide** **metolazone** K^+^ Sparing Diuretics prevent K^+^ secretion by blocking aldosterone antagonist at mineralocorticoid receptors **spironolactone** **eplerenone** inhibit Na^+^ influx in luminal membrane **amiloride** **triamterene** increase GFR and blunt Na^+^ reabsorption **nesiritide** Osmotic Diuretics absorb water and retain this water in the tubules **mannitol** ADH Antagonists excess ADH secretion causes water retention **conivaptan** **tolvaptan** **demeclocycline** **Renal Autacoids** **Adenosine:** ribonucleoside hypoxia (lack of oxygen) in the kidney causes rise in adenosine production hypoxia in the kidney = deceased GFR and decreased blood flow **Prostaglandins:** required for normal kidney function NSAIDs that inhibit prostaglandin synthesis in the kidney can lead to kidney failure **Peptides:** natriuretic peptides (coming up later), see above for **nesiritide** **THE DRUGS:** **Carbonic Anhydrase (CA) Inhibitors:** enzyme found mostly in the PCT, enzyme catalyzes the following CO~2~ +H~2~O ⇔ H~2~CO~3~ inhibition of this enzyme blocks the reabsorption of H~2~CO~3~ which leads to diuresis discovered in 1937, derivatives of sulfonamide (think sulfa allergy) prototypical CA inhibitor **acetazolamide** drugs increase urine pH (important in Chapter 1 on ion trapping to remove drugs from the body) MOA, depresses bicarbonate (HCO~3~^-^) reabsorption in the PCT Clinical Uses: glaucoma decrease intraocular pressure by blocking formation of aqueous humor in the eye **brinzolamide** urine alkalinization make urine alkaline (pH above 7.0) to ion trap drugs metabolic alkalosis **acetazolamide** to correct increased blood volume levels acute mountain sickness weakness, dizziness, insomnia, headache and nausea not fun when mountain climbing above 3000 m (\~ 9800 feet) can increase to pulmonary and cerebral edema **acetazolamide** is the go to drug, climbers carry it with them in their first aid kits ADRs, **Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors:** This pump reabsorbs almost 90% of the glucose that is filtered through the glomerulus into the collecting duct urine inhibit this pump with **dapagliflozin** or **canagliflozin** and glucose remains in the urine and is not reabsorbed used to treat diabetes mellitus **Adenosine A~1~ Receptor Antagonists:** **caffeine** is an adenosine antagonist and acts as a diuretic **Loop Diuretics:** these diuretics inhibit NaCl reabsorption in the TAL "most efficacious diuretic agents currently available" Katzung, pg 270 **furosemide,** a sulfa derivative and **ethacrynic acid not** sulfa derived (think no allergy) these drugs also promote excretion of calcium and magnesium, and may be used to treat hypercalcemia major clinical uses include acute pulmonary edema, acute hypercalcemia ADR can include increased uric acid levels which can cause gout, all except **ethacrynic acid** can cause a sulfa allergic reaction **Thiazides:** inhibit NaCl in the DCT, **hydrochlorothiazide** all of the thiazides have a sulfa group in their molecular structure ADR, may block uric acid secretion and raise plasma uric acid levels, may elevate blood glucose levels, hyponatremia, sulfa allergic reactions possible Clinical uses include hypertension (reduce blood volume), heart failure, kidney calcium stone formation, nephrogenic diabetes insipidus **Potassium-Sparing Diuretics:** all of the above diuretics cause loss of potassium, everyone expects us to know which diuretics do not cause loss of potassium Aldosterone, steroid hormone produced by the adrenal glands, this hormone promotes the reabsorption of sodium, water follows sodium, blood volume goes up, this leads to increased blood pressure. **spironolactone** and **eplerenone**, act as antagonists at aldosterone receptors in the kidney **amiloride** and **triamterene**, both block the sodium channel and keep sodium from being reabsorbed These drugs are "potassium-sparing" because they prevent potassium from being secreted ADRs, can cause hyperkalemia, gynecomastia is possible (drugs are steroid hormone analogs) **Osmotic Diuretics:** absorb water in the tubules and prevent this water from being reabsorbed back into the blood **mannitol**, is an osmotic diuretic administered IV only IV mannitol can also be used to treat intracranial and intraocular pressure **Antidiuretic Hormone (ADH) and Vasopressin Agonists:** Antidiuretic hormone (ADH) is most often called vasopressin. Vasopressin is a peptide hormone that is released by the posterior pituitary gland in response to falling blood pressure (BP). Vasopressin binds to V~1~ receptors on vascular smooth muscle and causes constriction (increased BP). Vasopressin also binds to V~2~ receptors in the renal tubule cells of the kidney and causes water to be reabsorbed into the body, increased blood volume, increased BP results. Diabetes insipidus is a disease condition in which vasopressin is decreased or no longer being produced. This results in massive loss of water, markedly increased urine output per 24 hours. An increase in the production of vasopressin results in water retention, low urine output. Two antagonist drugs are used to block the V~2~ kidney receptors and block the actions of vasopressin to take back water, **conivaptan** (IV only) and **tolvaptan** (PO). Chapter 15 DIURETICS (The required drugs are in **BOLD and in the list of required drugs above).**) **[DRUG CLASS ACTIONS LOCATION DRUGS ]** Carbonic Anhydrase Inhibitors Block reabsorption of NaHCO~3~ PCT **acetazolamide** dichlorphenamide methazolamamide SGLT Inhibitors Inhibit sodium/glucose transporter PCT **dapagliflozin** **canagliflozin** Loop Diuretics Inhibit NaCl reabsorption TAL **furosemide** **ethacrynic acid** **bumetanide** torsemide Thiazide Diuretics Inhibit NaCl reabsorption DCT **hydrochlorothiazide** bendroflumethiazide hydroflumethiazide metolazone trichlormethiazide Potassium Sparing Diuretics Prevent K^+^ secretion by blocking aldosterone Osmotic Diuretic absorbs water and retains it in the tubules **mannitol** ADH Antagonists excess ADH secretion causes water retention **conivaptan** **tolvaptan** demeclocycline