Diuretics and Lipids

Diuretic Agents Each diuretic agent acts upon a single anatomic segment of the nephron

Diuretic Agents Because the segments have distinct transport functions, the action of each diuretic can be best understood in relation to its site of action in the nephron and the normal physiology of the segment

Notice the body increases the “filtration rate” by constricting the efferent arteriole

The purpose of the collection system is to reabsorb salts, nutrients and water from the filtrate.

The purpose of the collection system is to secrete toxins not already in the filtrate

Thiazide Diuretics Hydrochlorothiazide

Thiazide diuretics inhibit NaCl reabsorption from distal convoluted tubule

Thiazide Diuretics Thiazides compete with secretion of uric acid This causes uric acid to go up, increasing the risk of gouty arthritis

Thiazide Diuretics Hypertension Congestive Heart Failure Nephrolithiasis due to hypercalciuria Diapetes insipidus

Thiazide Toxicity HypoKalemia (low potassium K+) HypoNatremia (low sodium Na+) Hyperuricemia (uric acid leads to gout)

Thiazide Toxicity Allergic reaction (sulfonamide cross reactivity) Photosensitivity

End in “zide” Many,many drugs used to treat HTN include hydrochlorothiazide in the combination

Loop Diuretics Furosemide (Lasix)

Loop Diuretics Selectively inhibit NaCl reabsorption in thick ascending loop of Henle

Loop Diuretics Most efficacious diuretics available-furosemide and ethacrynic acid Rapid acting, relatively short duration

Lasix The onset diuresis following oral administration is within 1 hour. The peak effect occurs within the first or second hour. The duration of diuretic effect is 6 to 8 hours.

Loop Diuretics Increase Ca++ and Mg++ excretion Reduce left ventricular filling pressure in CHF and pulmonary congestion

Loop Diuretics Acute pulmonary edema Acute renal failure – increase renal blood flow and enhance potassium excretion

Toxicity of Loop Diuretics Hypokalemia Hyperuricemia Hypomagnesemia Allergic reaction (furosemide is related to sulfonamide group) Hypovolemia

K+ Sparing Diuretic Spirinolactone Antagonizes aldosterone at late distal tubule and cortical collecting tubule Used in states of aldosterone excess (CHF, cirrhosis, nephrotic syndrome)

K+ Sparing Diuretic Spironolactone Toxicities include: severe hyperkalemia, gynecomastia and hyperchloremic metabolic acidosis

K+ Sparing Diuretic Spironolactone Hyperkalemia is a major complication - should not be use with ACE inhibitor

Osmotic Diuretics Nonreabsorbable solute pulls water into urine and increases urine volume Used to maintain urine volume and reduce intracranial and intraocular pressure IV

Toxicity of Osmotic Diuretics Extracellular volume expansion which may complicate heart failure and produce pulmonary edema Dehydration and hypernatremia

ADH Antagonists Only available agents are non-selective - lithium salts and demeclocycline - exact mechanism unknown

Carbonic Anhydrase Inhibitors Enzyme in proximal tubule that allows reabsorption of sodium bicarbonate Inhibitors reduce bicarb reabsorption and thus produce alkaline urine

Carbonic Anhydrase Inhibitors Acetazolamide – used to treat glaucoma by reducing rate of aqueous humor formation Also used to prevent acute “mountain sickness”

Toxicity carbonic anhydrase inhibitors Hyperchloremic Metabolic Acidosis Renal stones (calcium salts insoluble at alkaline pH) Potassium wasting

Hyperlipidemia and Atherosclerosis

Atherosclerosis

Prevalence of CAD Coronary artery disease 23% of americans 42% of all deaths annually

Prevalence of CAD M.I. – 1.5 million (500,000 fatal) Angina – 5.6 million (1,290 fatal) If CAD was eliminated life expectancy would rise approximately 10 years

Classes of Lipoproteins Chylomicrons – transport lipids from GI to liver

Classes of Lipoproteins LDL – transport lipids from liver to body - “bad cholesterol”

Classes of Lipoproteins HDL – transfers lipids from body back to liver - “good cholesterol”

Lipid Panel (lab test) Total cholesterol LDL HDL Triglyceride

Primary Hyperlipidemia Familial Hypercholesteremia Familial Hypertriglyceridemia Familial Hyperlipidemia

Secondary Hyperlipidemia Diabetes mellitus Nephrotic syndrome Uremia Hypothyroidism Obstructive liver disease Alcoholism Medication induced

Risk Factors Evidence of CAD HDL <40 Family history of premature CAD Smoking Hypertension Diabetes mellitus

Goal is to lower LDLs If no CAD and less than 2 risk factors - LDL less than 160

Goal is to lower LDLs If no CAD but 2 or more risk factors - LDL less than 130

Goal is to lower LDLs With CAD - LDL less than 100

Therapeutic Lifestyle Changes Diet Increase physical exercise Weight reductions Alcohol reductions Smoking cessation Control hypertension Control diabetes

Pharmacologic Agent Nicotinic Acid, Niacin, Vit. B3 - Niaspan

Nicotinic Acid Should be avoided in patients with: - active or chronic liver disease - peptic ulcer disease - diabetes - gout

Nicotinic Acid Take with food Do not take with hot liquids - taking ASA 325mg 30 minutes prior to dose may reduce flushing

Nicotinic Acid Side effects - flushes - pruritus - rash - nausea - heartburn - diarrhea

Nicotinic Acid Side Effects Headache Hypotension Liver dysfunction Glucose intolerance Hyperuricemia Exacerbation of peptic ulcer disease

Nicotinic Acid Drug interactions - statins (myopathy, rhabdomyolysis) - fibrates (myopathy, rhabdomyolysis)

Nicotinic Acid Monitoring - FBS - Liver Function Tests - AST - ALT Uric Acid

Bile Acid Sequestrants Cholestyramine Anion exchange resin Lowers LDL cholesterol May increase triglyceride

Bile Acid Sequestrants Side effects - bloating - abdominal pain - constipation - flatulence - nausea

Bile Acid Sequestrants Drug Interactions - binds to other medications, decreasing absorption (i.e., Warfarin, Coumadin) Take 1 hour before or 4 hours after the bile acid sequestrant

Fibric Acids Gemfibrozil - Lopid® Fenofibrate - Tricor® Biggest effect is lowering triglycerides by increasing lipolysis

Fibric Acids Side Effects - abdominal pain - nausea - diarrhea - muscle aches

Fibric Acids Drug interactions - HMG-CoA Inhibitors (statins) – increase risk of myopathy, rhabdomyolysis and acute renal failure - Niacin (myopathy) - Warfarin Coumadin (blood thinner)

Fibric Acids Monitoring - Liver Function Tests (LFT) – ALT, AST - CBC periodically

HMG Co-A Reductase Inhibitors “Statins” Lovastatin – Mevacor® Simvastatin - Zocor® Pravastatin - Pravachol® Fluvastatin - Lescol® Atorvastatin - Lipitor® Risurvastatin – Crestor®

HMG Co-A Reductase Inhibitors Inhibits the enzyme HMG Co-A reductase - required for cholesterol synthesis

HMG Co-A Reductase Inhibitors Inhibits the enzyme HMG-CoA reductase Required for cholesterol synthesis Decrease LDL and TG, some increase in LDL Avoid in patients with: - active for chronic liver disease - persistent elevation in LFT’s - pregnancy, lactation and women of child- bearing age

HMG Co-A Reductase Inhibitors Side Effects Gastrointestinal Hepatotoxicity Myopathy (muscle aches, weakness) Insomnia Headache Rash

Monitoring Liver Function Tests AST ALT