• Thiazides
• Loop
• Potassium sparing
• Aldosterone antagonists
• Carbonic anhydrase inhibitors
• Agents altering water excretion

• Where sodium goes, water follows
• 65-70% of all sodium is reabsorbed from the proximal tubule into the bloodstream; 20-25% in loop of Henle, 5-10% in the distal tubules, and 3% in collecting ducts
• sodium not absorbed is excreted in urine

• Hydrochlorothiazide (Hydrodiuril)
• Chlorothiazide (Diuril)
• Chlorthalidone (Hygroton)*
• Indapamide (Lozol)*
• Metolazone (Zaroxolyn)*

• Inhibits the Na+ Cl- symport, therefore inhibit NaCl reabsorption from the distal convoluted tubule and increase excretion
• ↑ K+ excretion in the distal convoluted tubule
• ↑ Ca+2 reabsorption from the proximal and distal convoluted tubules (hypocalciuric effect)
  
• ↓ uric acid excretion (competitive inhibition of uric acid excretion)
• slight ↑ in Mg+2 excretion

↓ K⁺, NaCl, Mg⁺²

↑ Ca⁺², uric acid

• Initially (1st month), the hypotensive effect occurs as a result of volume contraction due to diuresis
• Later, hypotensive effect is still seen, however it is not due to diuresis. Chronic hypotensive action due to arteriolar vasodilation (↓ peripheral vascular resistance)

1. Hypertension: in patients with adequate kidney fxn (Clcr > 30 ml/min)
2. Edema
3. Nephrogenic Diabetes Insipidus - in these patients urine output will ↓ with thiazide use

• Natriuretic effect of thiazides is dependent upon sodium reaching the distal tubule. 
• This may not occur in pts with severe renal disease (Clcr < 30 ml/min), CHF or cirrhosis, thiazides may be ineffective 

HCTZ = 12-16 hrs

Chlorthalidone = 24-72 hrs

Indapamide = up to 36 hrs

Metolazone = 12-24 hrs

* on mg to mg basis, chlorthalidone is 2x as potent as hydrochlorothiazide (HCTZ)

can effect:

1. Metabolic / endocrine system
2. Skin

Hyponatremia, hypokalemia, metabolic (contraction) alkalosis, hyperuricemia, hyperglycemia, hyperlipidemia, sexual dysfunction

- metabolic alkalosis: when volume is lost, Na is lost therefore Cl is lost. Cl is indicator for met. alkalosis/acidosis

- Hyperglycemia: worry about only in diabetics

- Hyperlipidemia: thiazides cause slight ↑ in LDL

Allergic reactions (thiazide and sulfonamide cross reactivity) 

• pts with sulfa allergies can have a sight rxn to thiazides

NSAID: some NSAIDs may ↓ the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics

- prostaglandins dilate vessels in nephron. NSAIDs block these prostaglandins therefore may block effects of thiazides

Lithium: Thiazides may induce lithium toxicity by ↓ its renal excretion

Bumetanide (Bumex)

Ethacrynic acid (Edecin) 

Furosemide (Lasix)

Torsemide (Demadex)

 sulfonamide derivatives:

Bemetanide

Furosemide

Torsemide

Non-sulfonamide derivative:

Ethacrynic acid 

• Inhibit Na⁺K⁺2Cl^- symport
• Selectively inhibit Na⁺ and Cl^- in the thick ascending loop
• b/c Mg⁺² and Ca⁺² reabsorption in the thick ascending limb is dependent on Na and Cl []s, loop diuretics also inhibitMg⁺² and Ca⁺² reabsorption 

↓ Na⁺, Cl^-, Mg⁺², Ca⁺²,K⁺

Cause more Na and Cl excretion than Thiazides b/c of where they act

• similar to thiazides, except:
• Effect on serum lipids and glucose is not as significant
• Hypomagnesemia (with prolonged use)
• Hypocalcemia is also possible
• Ototoxicity (ethacrynic acid> furosemide > bumetanide > torsemide)
  • ototoxicity seen with IV route
  • occurs most frequently with rapid administration
  • Related to peak concentration
  • Reversible

Ringing in the ears

• Decrease volume overload (decrease preload) in situations as heart failure or edematous states
• Acute renal failure (Where patient is not hypovolemic or dehydrated)
• Promote Ca⁺² diuresis in hypercalcemia (used with 0.9% NaCl infusion)

Loop: more potent for fluid loss therefore use for edema, CHF, cirrhosis...

Thiazides: use for hypertension

1. Triamterene & Amiloride
2. Aldosterone Antagonists: Spironalactone & Epirerenone

• Inhibit the renal epithelial (principal cells) Na+ channels in the late distal tubule and collecting duct. Therefore, ↑ excretion of Na+ and Cl- and ↓ secretion of K+
• Blockade of Na+ channels hyperpolarizes the luminal membrane, ↓ the lumen negative transepithelial voltage that is usually necessary for secretion of K+ into the lumen
• End result = inhibition of distal tubular K+ secretion

↓ Na+, Cl- (slight loss)

↑ K+

Rel. Potency Oral bioavailability   elim*

Amiloride: 1 15-25% R

Triamterene: 0.1  50% M

R= renal excretion of intact drug

M= metabolism

• Seldom used as sole agents in the treatment of edema or hypertension, due to their mild natriuresis
• Used in combination to offset the kaliuretic (K+ wasting) effects of thiazide and loop diuretics

• Hyperkalemia (avoid or use extreme caution in pts. with renal failure, receiving other K+ sparing diuretics, taking angiotensin-converting enzyme inhibitors, or taking K+ supplements)
• metabolic acidosis, By inhibiting H+ secretion (parallels K+ secretion) 
• GI side effects (minor)

• Ace inhibitors, K+ supplements = hyperkalemia
• NSAID = ↓ diuretic effects, hyperkalemia
• Pentamidime and high dose Trimethoprim = Hyperkalemia

• Spironolactone (Aldactone) 
• Eplerenone (Inspra) {has advantage because of effects on receptors}

• Competitively inhibit the binding of aldosterone to the mineralocorticoid receptors located in the late distal tubule and collecting ducts, therefore block the biological effects of aldosterone
• clinical efficacy is a fxn of endogenous levels of aldosterone 

• Spironolactone has some affinity toward progesterone and androgen receptors (induces gynecomastia, impotence, and menstrual irregularities). Eplerenone has very low affinity for these receptors
• Technically considered K+ sparing agents but are classified separately b/c:
  • more potent antihypertensives
  • slow onset of activity
  • evidence supporting compelling indications

• Hyperkalemia (eplerenone has greatest propensity of all K+ sparing agents, due to more selective aldosterone antagonist activity. Mild metabolic acidosis possible)
• Gynecomastia (occurs in up to 10% of pts. receiving spironolactone, but rarely with eplerenone)
• GI
• Skin

Include:

• Acetazomamide (Diamox) 
• Methazolamide (Mikart)
• both have sulfonamide structure 
• not used as diuretics b/c effects are very short lived

• CAI inhibit NA+ reabsorption by reversibly inhibiting proximal tubule cytoplasmic and luminal carbonic anhydrase
• inhibition of carbonic anhydrase leads to ↑ excretion of sodium bicarbonate (NaHCO₃) (can lead to acidosis)
• 85-90% of bicarbonate reabsorption occur in the proximal tubule
• NaHCO₃ resorption in proximal tubule is dependent on carbonic anhydrase
• prevent reabsorption of NaHCO₃ and cause diuresis

• Hyperchloremic Metabolic Acidosis: due to excessive excretion of HCO₃^-. Unlike diuretic effect, persists as long as drug is continued
• Kidney stones: HCO₃^- excretion (alkaline urine pH) causes excretion of Ca²⁺ and Phosphate = insoluble in alkaline pH 
• Sulfonamide type adverse rxns
• CNS: paresthesias (esp tingling in extremities), hearing dysfunction or tinnitus, loss of appetite, taste alteration

• diminishes over the course of several days of therapy
• due to compensatory up-regulation of NaHCO₃ reabsorption across more distal nephron segments (not well understood)

•  Glaucoma: (as eye-drops) ↓ IOP (dorzolamide, brinzolamide)
• urinary alkalinization: ↑urinary pH and excretion of weak acids is enhanced. (lasts only a few days)
• Metabolic alkalosis: short course used to rapidly correct diuretic-induced metabolic alkalosis. Also used in ventilated COPD pts. with CO₂ retention (hypercapnia) = ↑ respiratory drive to ↑ ventilation

• main agent = mannitol (osmitrol)
• excreted unchanged by glomerular filtration w/in 30-60 min., w/out any important tubular reabsorption or secretion
• proximal tubule and descending limb of Henle are freely permeable to water, so mannitol causes water to be retained with in these segments and promotes a water diuresis

Clinical indications and uses of mannitol

• reduce intracranial pressure or cerebral edema in certain necrologic conditions (IV)
• maintain urine volume and prevent anuria (not used clinically for these indications)
• promotion of urinary excretion of toxins

Adverse effects of mannitol

• fluid and electrolyte imbalance
• acute renal failure (in anuric pts.)
• local pain and venous irritation

• Very effective at ↓ BP when used in combo with most other anti-hypertensive agents b/c:

1. different mech. of action result in additive or synergistic effects
2. compensatory ↑ in Na and H2O retention may be seen with anti-hypertensive agents, diuretics counteract this effect

To minimize the risk of nocturnal diuresis:

• once daily: give in morning
• twice daily: give in morning and afternoon

• Metolazone is usual thiazide-like drug used in patients refractory to loop agents alone, but other thiazides likely to be as effective
• Watch for hypokalemia

• Renin acts on angiotensinogen (a protein substrate synthesized in liver)
• Renin is synthesized, stored and released by the juxtaglomerular cells in kidney
• majority of Ang I is converted to Ang II 1º by ACE, non-ace pathways (escape pathways) exist and modulate prod of Ang II
  • Highest [ACE] exists within endothelial cells (blood vessels) and pulmonary circulation

1. renal vascular receptors (stretch receptors) in the juxtaglomerular cells
2. Macula Dense (specialized cells in distal tubule that are sensitive to ionic content and water volume of the fluid)
3. sympathetic activity (mediated by β₁ adrenoreceptors)
4. Angiotensin II (via neg. feedback Mech)
5. Drugs

1.  Influenced by: 
   • vasodilators 
   • β₁ agonists
   • β₁ blockers
   •  diuretics
2. Inhibited by:
   • ACEI (angiotensin I → angiotensin II)
   • ARB (Angiotensin II → Angiotensin 1 type receptor; AT₁)
   • DRI (Angiotensinogen → Angiotensin I)

• alternative pathway for the conversion of Angiotensin I to Angiotensin II
• Carried out by Chymases or Gathepsin
• probably not a major pathway that contributes to angiotensin II production

1. Angiotensinogin → Angiotensin I (By Renin; inhibited by DRI)
2. Angiotensin I → Angiotensin II (by ACE; inhibited by ACEI)
3. Angiotensin II → Angiotensin receptors AT₁ and AT₂ (AT₁ blocked by ARB)

Include:

• arterial vasoconstriction (pressor effects)
• aldosterone secretion from the adrenal gland (↑ Na and H2O retention)
• Inhibition of renin secretion via neg feedback loop, ↑ renal Na reabsorption

Catalyzes:

• synthesis of angiotensin II
• destruction of bradykinin

• peripheral vasodilator (↓ BP)
• Stimulate prostaglandin synthesis (vasodilation and ↓ BP)
• Enhance insulin sensitivity (minor)

1. AT₁ 
2. _AT2

• Blocked by angiotensin receptor blockers (ARB)
• responsible for most known actions of Ang II, such as vasoconstriction, Na/H2O reabsorption, aldosterone secretion, sympathetic stimulation, cell growth

All have -pril somewhere in drug name, ie:

• Benazepril (Lotenisin)
• Captopril (Capoten)
• Enalaprilat (Vasotec IV)
• Lisinopril (Prinivil, zestril)

Mech of action of ACE inhibitors (ACEI)

1. Prevent the conversion of Ang I to Ang II by inhibiting ACE
2. Inhibit breakdown of bradykinin (potent vasodilator) and, therefore stimulate the actions of bradykinin, PGI₂, and PGE₂ (Which are all vasodilators and ↓ BP)

1. Hypertension
2. Heart failure & post MI
3. Prevention of diabetic nephropathy

• ↓ BP (due to suppression of the vasoconstrictor Ang II and potentiation of the vasodilator bradykinin)
• Patients with high renin states (dehydration, ↓ salt intake, renovascular hypertension, CHF, liver disease, or diuretic-induced volume [ ]) may be more sensitive to the effects of ACEI
• no good correlation among subjects between plasma renin activity and anti-hypertensive response. Accordingly, renin profiling is unnecessary

• Prevent left ventricular hypertrophy by ↓ direct effects of Ang II on myocytes
• Prevent ventricular dilation and remodeling caused by loss of myocytes post MI (when myocytes are damaged elasticity is lost, ACEI inhibit this damage. Early use is best, after damage is present effects of ACEI is greatly ↓)
• Other hemodynamic effects include significant ↑ in cardiac index, stroke volume index, and significant ↓ in lift ventricular filling pressure, SVR, MAP,and heart rate
• Significant improvements in clinical status, functional class, exercise tolerance, and left ventricular size 

• ACEI diminish proteinuria and stabilize renal fxn (even in absence of lowering BP)
• these benefits probably result form improved intra-renal hemodynamics, with ↓ glomerular efferent arteriolar resistance and a resulting ↓ of intra-glomerular capillary pressure

• food ↓ absorption of Catopril and Moexipril. Take 1 hour before meals
• Most ACEI, except Catopril and lisinopril, are prodrugs (rapidly converted to their active metabolites following oral administration)
• slow onset of action
• long duration of action, allowing for mostly once-a-day dosing (except Catopril)
• assessment of action should be done 3-4 weeks after initiating therapy

• Target doses (tested maximal doses) were documented to improve morbidity and mortality in pts. with heart failure or MI
• Target doses should be achieved/attempted in at lease these patients. Otherwise try the highest tolerated dose. Barriers include tolerability/side effects, and prescriber education
• addition of thiazides sig. ↑ anti-hypertensive efficacy (add in slow increments)

• Angioedema
• Hypotension
• Hyperkalemia
• Cough
• Renal function impairment
• other miscellaneous effects

• may affect face, extremities, lips, tongue, mucous membranes, glottis, or larynx. Intestinal angioedema should be in the differential diagnosis of ACEI pts. presenting with abd pain. 
• may occur at any time during treatment
• may be fatal due to airway obstruction
• pts with history of angioedema unrelated to ACEI therapy may be at ↑ resk of angioedema while on ACEI
• more common in african-americans and smokers

• occurs at onset of therapy and may occur following first dose
• ↑ renin state pts at risk include: Heart failure, hyponatremia, high-dose diuretic therapy, recent intensive diuresis or ↑ in diuretic dose, renal dialysis, or severe volume and/or salt depletion 
• hypotension is not a reason to discontinue ACEI
• start at low dose and ↑ slowly to reduce these effects

• may raise serum K+ by at least 0.5 mEq/L
• rarley a reason to discontinue ACEI therapy
• Risk factors for development of hyperkalemia include: renal insufficiency, diabetes mellitus, and concomitant use of agents that ↑ serum potassium (eg. K+ sparing diuretics, K+ supplements, and/or K+ containing salt substitutes)

• Chronic cough has occurred with use of all ACEI. Incidence range of 5-25%
• due to inhibition of the degradation of endogenous bradykinin (a pulmonary irritant)
• cough is nonproductive, persistent and resolves within 1-7 days (may take as long as 2 weeks) after discontinuation
• higher incidence in women
• if ACEI used for a compelling indication, switch to an ARB

• attributed to inhibition of Ang II vasoconstriction on the efferent arteriole. ↑ in serum creatine of up to 35% may not require discontinuation of therapy
• Pts with unilateral or bilateral renal artery stenosis are dependent on vasoconstrictive effects of Ang II on the efferent arteriole of the kidney. There is ↓ afferent blood flow, the intra-glomerular pressure and glomerular filtration are maintained by Ang II mediated efferent vasoconstriction
• Ang II causes vasoconstriction of both afferent and efferent arterioles, (preferential effect of efferent side). Under physiologic conditions, efferent tone is essential to maintain intra-glomerular pressure and GFR
• In renal artery stenosis, there is a ↓ afferent blood flow, removal of the efferent vasoconstriction effect by ACEI may ↓ GFR

• Neutropenia associated with Captropril occurs in 1 of 8,600 exposed. Neutropenia, leukopenia, and agranulocytosis have occurred rarely with other agents. Pre-existing kidney or connective tissue diseases ↑ this risk
• Hepatic fxn impairment could develop with markedly elevated plasma levels of unchanged fisinopril, meoxipril or ramipril
• Photosensitivity
• Contraindicated in Pregnancy

Include:

• Candesartan (atacand)
• Eprosartan (Teveten)
• Irbesartan (Avapro)
• Losartan (Cozaar)

• selectively block the binding of ang II to the AT₁ receptor in many tissues (eg., vascular smooth muscle, adrenal gland)
• Much greater affinity for AT₁ than AT₂ 
• In contrast to ACEI, ARB permit Ang II activation of AT₂ receptors
• Inhibit Ang II form all pathways (ACE and non-ACE)
• do not block breakdown of bradykinin
• little effect on serum K+

• Inhibit AT₁ and stimulate AT₂ 
• Both these actions cause vasodilation (positive effect)

• Most agents have long T1/2 to allow once daily dosing. However, Candesartan, eprosartan, and losartan have the shortest t1/2 and may require twice dosing for sustained BP lowering
• mostly undergo hepatic metabolism. Candesartan undergoes minor hepatic metabolism. Olmesartan is not metabolized
• Candesartan is a prodrug, activated during absorption from GI tract
• Losartan has an active metabolite

• Have a fairly flat dose response curve, suggesting that ↑ the dose above low or moderate levels is unlikely to result in a large degree of BP lowering
• Addition of thiazides sig.↑ anti-hypertensive efficacy

• Diabetic nephropathy: ARB at least = efficacy to ACEI due to renoprotection (improved intra-renal hemodynamics) and possibly improved insulin sensitivity effects through other mechanisms
• Heart Failure: ARB are reasonable alternatives to ACEI as 1st line therapy for pts with mild to moderate HF and ↓ LVEF, especially for pts already taking ARBs for other indications
• b/c of above 2 indications ARBs are as effective as ACEIs
• Post MI (possibly as beneficial as ACEI)
• Hypertension (probably similar efficacy, but no long term direct comparisons)

• Renal insufficiency (including pts with HF, salt or volume depletion, or renal artery stenosis)
• Hyperkalemia (little effects)
• Orthostatic hypotension
• cough (very uncommon): switching pts who cough from ACEI to ARB is a reliable way to avoid
• angioedema (rare) (generally considered safe in pts with ACEI induced angioedema)
• ARBs may be slightly better than ACEIs with regards to side effects, esp for cough or angioedema
• Do not use during pregnancy

• ARBs may be slightly better than ACEIs with regards to side effects, esp for cough or angioedema, not efficacy

• to avoid the escape phenomenon  (incomplete suppression of Ang II) with ACEI monotherapy
• additive effects in diabetic nephropathy and HF

Combination therapy may ↑ the incidence of the following side effects, especially in pts with LV dysfunction (HF):

• Hypotension
• Hyperkalemia
• Renal impairment

• Products: 
  • Aliskiren (Tekturna)
  • Aliskiren/valsartan (Valturna)
  
  
  New class of drugs, clinical use unclear

• Bioavailability = 2.5%
• Protein binding = 40%
• mostly metabolized by CYP3A4
• excreted as metabolites via renal and biliary route

• Diarrhea (GI irritation)
• Abdominal pain, dyspepsia
• cough (lower than ACEI)
• angioedema (? comparable to ACEI)
• ↑ uric acid

• ACEI and ARB do not produce complete RAAS inhibition
• Aliskiren blocks the RAAS at its point of activation

Limitations of aliskiren

• Dose > 300mg/day do not ↑ efficacy and may cause diarrhea
• lower bioavailability if taken with fatty meal
• reduces the effects of furosemide
• contraindicated in pregnancy