Exam 3- Diuretics Flashcards
1
Q
Why do you have to care about the pharmacology of diuretics?
A
- Diuretics are very effective in treating pulmonary edema in congestive heart fialure patients
- Diuretics are used to prevent epistasis and pulmonary hemorrhage in racehorses
- Diuretics are commonly used for controlling high blood pressure.
2
Q
How much blood does the kidney filter in a day
A
180 Liters per day. Total blood volume gets filtered every 40 min; 36 times a day.
3
Q
What is the funciton of diuretics?
A
Increase the water and salt elimination rate in the urine
4
Q
What are the major pharmacological effects of diuretics/
A
- Increase renal excretion of mainly Na+ and water
- Decrease extracellular fluid volume
- Normlaize blood pressure and improve cardiac function
- Restore normal tissue perfusion and organ function
- Enhance the clearance of poisons, drug and metabolites
- increase clearance of debris from nephrons
5
Q
What are causes of generalized edema (in relation to edema and diuretic use)
A
- Congestive heart failure- decreased cardiac output - renal hypofunction - RAS activation - Na and H20 retention - edema
- Nephrotic syndrome- Protein loss in urine- decreased plasma oncotic pressure- increased interstitial fluid
- Hepatic disease- decreased aldosterone or protein synthesis
6
Q
What are examples of local edema in relation to localized edema
A
- Cardiogenic pulmonary edema: cardiomyopathy, valve and septal defects
- Hypertension
- others such as glaucoma, Ca. urolithiasis
7
Q
What is the location of the primary site of action in Osmotic diuretics
A
- Primary site of action is the proximal tubule and descending loop
8
Q
Osmotic Diuretics- mechanism of action
A
- Osmotic diuretics are filtered into the nephron at the glomerulus; however they cannot be reabsorbed from the nephron and thereby forms osmotic gradient. The osmotic activity of these agents prevents water and ionic reabsorption and thus causes diuresis.
9
Q
What type of drug is Manitol
A
This is an Osmotic diuretic- this is given in a solution of various concentrations
- Most commonly used by IV route only; used short-term and in emergency situations
10
Q
What type of drug is Glycerin
A
This si an osmotic diuretic that is orally absorbed, used up to 50% solution
11
Q
What type of drug is Isosorbide?
A
Osmotic diuretic- orally absorbed and used up to 50% solution
12
Q
What are the pharmacokinetics of osmotic drugs:
A
Short half-life excreted unmetabolized drug
13
Q
What are the theraputic uses of Osmotic diuretics
A
- Cerebral edema: mannitol is very effective for reducing intracranial pressure
- Acute glaucoma: in dogs and cats, mannitol or glycerin reduces intraocular pressure (IOP). Used for acute glaucoma attacks before and after ophthamotic surgery; isorbide is preferred for diabetic patients
- Renal failure: Mannitol is used as an adjunct to furosemide to increase glomerular filtration volume and maintain urine flow; used to treat ischemia or nephrotoxin induced acute tubular necrosis
- Poisonings: Mannitol is used for elimination of poisons in dogs and cats.
14
Q
What are the adverse effects of osmotic diuretics:
A
- Mannitol is not recommended for animals with pulmonary edema because it can extract water from the intracellular compartments and expand in the extracellular fluid in the lung.
- Mannitol is not recommended in animals with cerebral hemorrhage, as the agent can increase fluid buildup resulting in intracranial pressure
- Osmotic diuretics rarely produce toxicity; but fluid and electrolyte balance should be monitored because mannitol produces a profound diuresis.
15
Q
What is the mechanism of action for Loop Diuretics?
A
- This is the most powerful and widely used diuretics
- Reduce ion reabsorption by inhibiting the Na+/K+/2Cl- cotransport in the luminal membrane of the thick ascending loop of Henle
- Also inhibit Ca2+ and Mg2+ reabsorption due to change in luminal positive potential
16
Q
What is the ancillary action for loop diuretics?
A
increase prostaglandins release
increase renal blood flow
decreased left ventricular pressure
Decreased pulmonary edema
17
Q
What type of drug is Furosemide (Lasix)
A
- This is the most common diuretic
- Na+ and water excretion by 17 fold
- In horses the drug increases urine from 2.6L to 14.3 L
18
Q
How is Furosemide (Loop Diuretic) metabolized?
A
This is absorbed well orally. Strongly bound to plasma proteins and so do not pass into the glomerular filtrate. Reach the site of action by being secreted into proximal convoluted dubule by organic acid transporter.
80% of unmetabolized drug is excreted in the urine 20% as glucuronide.
19
Q
How does Torsemide compare to Furosemide?
A
This is a loop diuretic that is twice as potent as furosemide
20
Q
How does Bumetanide compare to Furosemide?
A
25-40 times more potent than furosemide
21
Q
What are the theraputic uses for Loop diuretics?
A
- Edema- rapid mobilization of edema. Furosemide is very effective for pulmonary edema
- Heart failure: most efficacious class of drugs used for congestive heart failure. Furosemide is used as a key combination therapy with other cardiovascular drugs for treatment of CHF
- Antihypertensive: in small doses
- Hypercalcemia- increased urinary Calcium secretion in dogs and cats. used for treatment of hypercalcemia of malignancy or vitamin D toxicosis
- hyperkalemic state. Used if mannitol is ineffective
- Treatment of post-parturient udder edema
- EIPH: in race horses to reduce eiph and epistaxis
- Furosemide increases blood flow and decreases the left arterial pressure
22
Q
how do you monitor the loop diuretics?
A
Evaluate serum electrolytes, BUN, creatinine, glucose, hydration status, BP and status of edema- X-ray and body weight.
23
Q
What are adverse effects of loop diuretics
A
- Fluid and electrolyte imbalance: Hypokalemia is the most common adverse effect. IN cHF patients, use K+ supplements or K+ sparing diuretics. Monitor serum electrolyte levels
- Symptoms of hypokalemia: dizziness, muscular weakness, cardiac arrhythmias, tetany, respiratory arrest, and coma.
- Ototoxicity: Loop diuretics may cause deafness due to electrolyte imbalances in the endolymph of the inner ear. Cats are very sensitive.
- Other side effectsL dehydration, hyperuriemia(Gout), hypocalcemia, muscle weakness, metabolic alkalosis, CNS depression
24
Q
What aer common drug interactions for Loop diuretics
A
- Loop diuretics exacerbate ototoxicity and nephrotoxicity of aminoglycaside antibiotics and cisplatin
- Increase hypokalemia when combined with corticosteroids or amphotericin B
- Furosemide inhibits uricosuric effects of probenecid or sulfinpyrazone. NSAIDS reduce diuretic response of loop diuretics. Furosemid may alter the requrirements of insulin and other anti-diabetic drugs
25
What are contraindications for use of Loop Diuretics?
Patients with hepatic dysfunction, gout, diabetes mellitus
26
What is the mechanism of action for Thiazide Diuretics?
* Inhibition of the Na+/Cl- symporter in the distal convoluted tubule.
* Increase in reabsorption of Ca2+ due to stimulation of Na+/Ca2+/ counter transporter
Result: increased urine concentration of NaCl and K+, decreased urine concentration fo Ca2+
27
What are examples of Thiazide diuretics?
* Chlorothiazide
* Hydrochorothiazide
* Trichlormethiazide
* Chlorthalidone
28
What is mechanism of drug metabolism for Thiazide diuretics
Absorbed well in all routes. In cats and dogs, diuretics response occurs 2-3 hours and last 12 hours. Mainly excreted via urine.
29
What are theraputic uses for Thiazide diuretics?
* The goal is to produce a moderate diuresis and is referred to as rescue diuretics
* Antihypertensive agent: Very effective and delayed onset (several days) and long term use. Combined formulation: hydrochlorothiazide + losartan=Hyzaar
* Used as an adjunct in the treatment of CHF in dogs and cats
* Treatment of post partuient udder edema in cattle: Nasquasone is approved drug. It can also be used to reduce mild leg swelling in horses
* Ca-oxalate Uroliths: decrease oxalate bladder stones in dogs
* Nephrogenic diabetes insipidus (NDI) in dogs: kidney becomes resistant to ADH and causes polyuria. Paradoxically, thiazides (hydrochlorothiazine) reduces urine outpur in dogs with NDI by increasing expression Aquaporin-2 water channels in the tubules
30
What are adverse effects and contraindications
* Fluid and electrolyte imbalance. Hypercalcemia with prolonged thiazide use
* Hypokalemia and hyperuricemia (Gout) \< compared to look diuretics
* Hyperglycemia and glucosuria: in diabetic and prediabetic animals, thiazides produce hyperglycemia and glucosuria by inhibiting the conversion of proinsulin to insulin
31
Should diabetics be given Thiazides?
No- avoid this because thiazides produce a hyperglycemia and glucosuria by inhibiting the conversion fo proinsulin to insulin
32
What are the effects of Potassium sparing diuretics?
* Na+ channel blockers
* Aldosterone antagonists
33
How do Na+ channel blockers work in reference to K Sparing diuretics?
* Amiloride and triamterene block Na+ channels. This reduces the luminal potential and the K+ secretion driving force for a decreased potassium excretion (K+sparing diuretic+)
* Also, reduction in the lumen negative potential decreases H+ secretion int he intercalated cells (can cause metabolic acidosis)
There is a net increase in Na+ secretion, and a Decreased K+, H+ secretion
34
What is the mechanism of action for Aldosterone antagonists?
Aldosterone antagonists competitively inhibit the binding of aldosterone to its receptors and thereby reduce the synthesis of Aldosterone- induced proteins (AID). Therefore, the antagonists inhibit the following functions of AIP:
* Synthesis of Na+/K+ channels
* Synthesis of Na+/K+ ATPase
* Mitochondrial ATP production
Net effect, increased Na+ secretion and a decreased K+, and H+ secretion
35
What are theraputic uses of K+ sparing diuretics?
Used in combination with potassium losing diuretics (loop diuretics and thiazides)
* **Chronic use for treatment of CHF:** used as an adjunct with loop or thiazide diuretics
* **Treatment of aldosteronism**: to counter the aldosterone-induced Na+ retention and K+ loss
* **Treatment of ascites**
36
What is a potential adverse effect for the use of K+ sparing diuretics?
Hyperkalemia and Metabolic acidosis
37
What is the mechanism of action for Carbonic Anhydrase Inhbitiors?
These are sulfonamide derivatives
The drugs inhibit carbonic anhydrase enzymes and reduce the number of hydrogen ions available for Na+/H+ exchange.
Result: increase NaHCO3 excretion
Increase K+ excretion
Increased Cl- RETENTION -\> hyperchloremic acidosis
38
What are the theraputic uses for Carbonic Anhydrase inhibitors?
**For Glaucoma:** inhibition of ciliary body CA decreases aqueous humor production
**For metabolic alkalosis:** Hyperkalemic periodic paralysis in horses
39
What are the mechanisms of action for Xanthines:
Xanthine increases the renal blood flow and increases the GFR -\> decreases the Na+ reabsorption in the proximal convoluted tubule.
40
What are the theraputic uses for Xanthines?
Rarely used soley for diuresis but increases urine output
41
What is the mechanism of action for Urinary Acidifiers?
Ammonium chloride lowers the pH of ECF and urine. The liver converts ammonium chloride to NH3, H+, Cl- and H+ is buffered by bicarbonate in plasma. The increased Cl- load to the kidney produces urinary loss of Na+ and Cl- and mild diuresis
Methionine -\> SO4 excretion in urine as H2SO4
42
What are the theraputic uses for Urinary Acidifiers
These are mixed with diets 2-3 times per day
* Promotes excretion of ionizable drugs or poisons by urinary acidification
* Urinary stone dissolutino and prevention
43
What classes of diuretics cause **Hypokalemia**?
Loop diuretics, Thiazide diuretics.
44
What diuretics can cause metabolic alkalosis?
Loop diuretics, Thiazide diuretics
45
What diuretic can cause hypocalcemia?
Loop diuretics
46
What diuretic can result in
47
What diuretic has the potential for producing a state of hypercalcemia?
Thiazide diuretics.
48
What can happen when either Thiazide or loop diuretics are used with NSAIDS?
Reduced diuretic response. Interaction is a result of inhibition of prostaglandin synthesis
49
What is the major drug inteaction for Potassium- sparing diuretics?
Angiotensin- converting enzyme inhibitors and K+ supplements
50
What occurs when Loop diuretics are associated with Aminoglycosides adn cisplatin?
increased risk of ototoxicity
51
What occurs when Thiazide and loop diuretics interact with Cardiac glycosides?
There is an increased risk of cardiac glycoside-induced arrhythmias
-hypokalemia potentiates action of cardiac glycosides
52
What are the key regulators of the RAAS system?
blood pressure
fluid volume
electrolytes
53
What occurs in the RAAS system?
Renin proudction is stimulated , eventually Aldosterone is produced and it encourages the retention of Na+, vasoconstriction occurs and K+ is excreted.
54
Where do ACE inhibitors work?
List examples of these drugs
The conversion of Angiotensin 1 to Angiotensin 2 is prevented.
Captopril
Enalapril
Lisinopril
55
Where do AT1 receptor blockers work
Prevent the conversion of Angiotensin II to Phospholipase C
56
What are examples of AT1 receptor blockers?
Losartan
Valsartan
57
What are the theraputic uses for ACE inhibitors and AT1 Receptor Blockers?
* use as vasodilators in heart failurein dogs and cats (used in combination with digitalis, furosemide)
* Treatment of hypertension
* Adjunctive treatment in chronic renal failure
* AT1 blockers reduce mortality associated in cardiac problems and may have anticancer and neuroprotective properties.
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