B4M1C1: Cardiovascular System Flashcards

Question

There is no dividing line between normal and higher blood pressure. Arbitrary levels have to be established to define persons who have an increased risk of developing a morbid cardiovascular event and / or will benefit from medical therapy. ● Should take into account:

Answer 1

level of diastolic pressure also systolic pressure, age, sex, race, and concomitant disease.

Answer 2

Essential Hypertension (Primary or Idiopathic)

Answer 3

Secondary Hypertension

Answer 4

Hypertensive Heart Disease

Answer 5

Labile Hypertension (Borderline Hypertension)

Answer 6

Accelerated Hypertension

Answer 7

Malignant Hypertension

Answer 8

Hypertensive crisis

Answer 9

Pseudohypertension

Answer 10

Whitecoat Hypertension

Answer 11

● Blood pressure increases steadily during the first two decades of life. ● Blood pressure is associated with growth and development in children and adolescents. ● During ***early adulthood***, average systolic blood pressure is **higher for men** than for women. ● Individuals ***aged 60 and older***, the systolic blood pressure is **higher in women** than in males.

Answer 12

● 30% of adults have hypertension with blood pressure of ≥140/≥90 ○ 33.5% in non — Hispanic blacks ○ 28.9% in non — Hispanic whites ○ 20.7% in Mexican Americans

Answer 13

● Filipino adults 20 years and above with hypertension ○ 2012 - 21% ○ 2008 - 21% ○ 2003 - 16%

Answer 14

Go back to notes 📝

Answer 15

1. **Decreased vascular compliance (arteriosclerosis)** 2. **Increased cardiac output FAPATH** - Fever - Aortic regurgitation - Patent ductus arteriosus - Arteriovenous fistula - Thyrotoxicosis - Hyperkinetic heart syndrome

Answer 16

**Renal:** Parenchymal diseases, renal cysts (polycystic kidney disease), renal tumors (renin-secretin tumors), obstructive uropathy **Renovascular:** Arteriosclerotic, fibromuscular dysplasia **Adrenal:** Primary aldosteronism, Cushing’s syndrome, 17a-hydroxylase deficiency, 11B-hydroxylase def, 11-hydroxysteroid dehydrogenase (licorice), pheochromocytoma **Aortic coarctation** **Obstructive sleep apnea** **Preeclampsia/eclampsia** **Neurogenic:** Psychogenic, diencephalic syndrome, familial dysautonomia, polyneuritis (acute porphyria, lead poisoning), acute increased intracranial pressure, acute spinal cord section **Miscellaneous endocrine:** Hypothyroidism, hyperthyroidism, hypercalcemia, acromegaly **Medications:** High-dose estrogens, adrenal steroids, decongestants, appetite suppressants, cyclosporine, tricyclic anti-depressants, monoamine oxidase inhibitors, EPO, NSAIDs, cocaine

Answer 17

SBP then DBP althroughout **N:** <120 / <80 **Prehypertension:** 120-139 / 80-89 **Stage 1:** 140-159 / 90-99 **Stage 2:** >=160 / >=100

Answer 18

***look at cmap B4M1C1***

Answer 19

Essential hypertension

Answer 20

Untreated hypertension

Answer 21

● Individuals who have relatively mild disease — i.e. without evidence of end organ damage — that is left untreated for 7-10 years

Answer 22

○ Nearly 30 % will exhibit **atherosclerotic complications.** ○ More than 50% will have **end organ damage** related to the hypertension itself, such as cardiomegaly, congestive heart failure, retinopathy, a cerebrovascular accident, and/or renal insufficiency.

Answer 23

***Genetic influences + Environmental factors*** **Defects in Renal Sodium Hemostasis** 1. Inadequate Na excretion 2. Na & water retention 3. Increase Plasma and ECF volume (can also increase Natriuretic hormone w/c can increase Vascular reactivity) 4. Increase Cardiac Output (autoregulation) 5. HYPERTENSION **Functional, Vasoconstriction** 1. Increase Vascular reactivity 2. Increase Total peripheral resistance 3. HYPERTENSION **Defects in Vascular Smooth Muscle Growth and Structure** 1. Increase Vascular wall thickness 2. Increase Total peripheral resistance 3. HYPERTENSION

Answer 24

**Genetic factors** Most studies support the concept that inheritance is probably multifactorial or that a number of different genetic defects each have an elevated blood pressure as one of their phenotypic expressions.

Answer 25

Gene defects in enzymes involved in aldosterone metabolism (e.g. **aldosterone synthase, Il B - hydroxylase, 17 a - hydroxylase**)

Answer 26

Liddle syndrome

Answer 27

Role of Intermediate Phenotype in Genetic Analysis Table 246-4

Answer 28

● Salt intake, obesity, occupation, alcohol intake, family size and crowding have been implicated in the development of hypertension. ● These factors have all been assumed to be important in the increase of blood pressure with age in more affluent societies, in contrast to the decline in blood pressure with age in less affluent groups. ● Salt intake is the environmental factor that has received the greatest attention. ○ Even this factor illustrates the heterogeneous nature of the essential hypertensive population, in that the blood pressure in only approximately 60% of hypertensive is particularly responsive to the level of sodium intake. ○ The cause of this special sensitivity to salt varies, with primary aldosteronism, bilateral renal artery stenosis, renal parenchymal disease, and low-renin essential hypertension accounting for about half the patients. ● Other postulated contributing factors include chloride intake, calcium intake, a generalized cellular membrane defect, insulin resistance and “non modulation.”

Answer 29

Volume status of the individual, particularly as related to changes in dietary sodium intake.

Answer 30

Angiotensin II

Answer 31

Prior dietary electrolyte intake

Answer 32

angiotensin Il

Answer 33

Adrenal responses: ***enhanced*** Renal vascular response: ***reduced***

Answer 34

Opposite of restriction

Answer 35

Hypertensive: broader

Answer 36

low renin and others as having high-renin essential hypertension

Answer 37

● Approximately 20% of patients who have essential hypertension have suppressed plasma renin activity. ● This is more common in individuals of **African descent** than in white patients. The patients have **expanded extracellular fluid volumes.**

Answer 38

○ Sodium retention and renin suppression are due to excessive production of an unidentified mineralocorticoid. ○ The adrenal cortex has an increased sensitivity to angiotensin Il — this could be the cause of hypertension

Answer 39

● Approximately 15% of patients with essential hypertension have plasma renin activity levels above the normal range. ● Has been suggested that plasma renin plays an important role in the pathogenesis of the elevated arterial pressure in these patients. ● Postulated that the elevated renin levels and blood pressure may both be secondary to an increase in adrenergic system activity.

Answer 40

● Substantial fraction of the hypertensive population has **insulin resistance and hyperinsulinemia.** ● ***Insulin resistance*** is common in patients with **non-insulin-dependent diabetes mellitus (NIDDM) or obesity.**

Answer 41

Both obesity and NIDDM

Answer 42

Hyperinsulinemia and insulin resistance

Answer 43

○ Hyperinsulinemia produces **renal sodium retention and increases sympathetic activity.** ○ **Vascular smooth muscle hypertrophy** ***secondary to the mitogenic action of insulin.*** ○ Insulin modifies ion transport across the cell membrane, thereby potentially **increasing the cytosolic calcium levels of insulin-sensitive vascular or renal tissue.** ○ **Insulin resistance** may be a marker for another pathologic process, e.g. non modulation, which could be the primary mechanism increasing blood pressure.

Answer 44

Non-modulators

Answer 45

● Concentric left ventricular hypertrophy characterized by an increase in wall thickness. ● Dilatation of left ventricular cavity ● Myocardial damage — ischemia or infarction ● P.E. findings: ○ Heart is enlarged ○ Prominent left ventricular impulse ○ Sound of aortic closure is accentuated, and there maybe a faint murmur of aortic regurgitation ○ Pre Systolic (atrial, fourth) heart sounds are frequent ○ Pre Diastolic (ventricular, third) heart sound or summation gallop rhythm may be present

Answer 46

● Retinal changes ○ Focal spasm and progressive general narrowing arteriole ○ Papilledema or hemorrhages of the macular area producing scotomata, blurred vision, and even blindness.

Answer 47

● **Cerebral infarction** which is secondary to the increased atherosclerosis. ● **Cerebral hemorrhage** which is the result of both the elevated arterial pressure and the development of cerebral vascular microaneurysms. ● Prominent symptoms: ○ Occipital headache ○ Dizziness ○ Light-headedness ○ Vertigo ○ Tinnitus ○ Dimmed vision ○ Syncope

Answer 48

● Arteriosclerotic lesions of the afferent and efferent arterioles and the glomerular capillary tufts ● Decreased glomerular filtration rate ● Tubular dysfunction ● Proteinuria and microscopic hematuria ● Renal failure

Answer 49

HYALINE ARTERIOSCLEROSIS & HYPERPLASTIC ARTERIOSCLEROSIS

Answer 50

HYALINE ARTERIOSCLEROSIS

Answer 51

HYPERPLASTIC ARTERIOSCLEROSIS

Answer 52

● To assess **lifestyle and identify other cardiovascular risk factors or concomitant disorders** that may affect prognosis and guide treatment ● To reveal identifiable **causes** of high BP ● To assess the **presence or absence of target organ damage and cardiovascular disease**

Answer 53

Components of the metabolic syndrome: 🫀 Hypertension 🫀 Obesity (BMI >/=30kg/m2) 🫀 Dyslipidemia 🫀 DM 🫀 cigarette smoking 🫀 physical inactivity 🫀 microalbuminuria or estimated GFR <60mL/min 🫀 age (>55 for men; 65 women) 🫀 fam hx of premature cardiovascular dse (men under age 55 or women under 65)

Answer 54

Heart 🫀 left ventricular hypertrophy 🫀 angina or prior myocardial infarction 🫀 prior coronary revascularization 🫀 heart failure Brain 🧠 stroke or transient ischemic attack Chronic kidney disease Retinopathy

Answer 55

Sleep apnea Drug-induced or related causes CKD Primary aldosteronism Renovascular disease Chronic steroid therapy and Cushing’s syndrome Pheochromocytoma Coarctation of the aorta Thyroid or parathyroid disease

Answer 56

● Most patients with hypertension have no specific symptoms referable to their blood pressure elevation. **● Common complaints are:** ○ Headaches localized to the ***occipital region*** and are present when the patient awakens in the morning but subside spontaneously after several hours. ○ Dizziness, palpitation, easy fatigability, and impotence which may be related to elevated blood pressure. ● Referable to ***vascular diseases include epistaxis, hematuria, blurring of vision owing to retinal changes, episodes of weakness or dizziness due to transient cerebral ischemia, angina pectoris, and dyspnea due to cardiac failure.*** ● A ***strong family history of hypertension*** favors the **diagnosis of essential hypertension.** ● A history of use of ***adrenal steroids or estrogen*** is of **obvious significance.** ● History of ***repeated urinary tract infection*** suggests **chronic pyelonephritis**; ***nocturia and polydipsia*** suggest **renal or endocrine disease.** ○ History of ***weight gain*** is compatible with **Cushing’s syndrome** and one of ***weight loss*** is compatible with **pheochromocytoma.** ● A number of aspects of the history aid in determining whether vascular disease has progressed to a ***dangerous stage***. These include **angina pectoris and symptoms of cerebrovascular insufficiency, congestive heart failure, and/or peripheral vascular insufficiency.** ● Other risk factors that should be asked about include ***smoking, diabetes mellitus, lipid disorders, and a family history of early deaths due to cardiovascular disease.*** ● Aspects of the patient's lifestyle that could contribute to hypertension or affect its treatment should be assessed including ***diet, physical activity, family status, work, and educational level.***

Answer 57

● General appearance - observe for ***facial expression and contours, and muscular development in the upper extremities.*** ● Appropriate measurement of BP, with verification in the **contralateral arm.** ● Examination of the **optic fundi** ● Calculation of **body mass index (BMI)** ○ Measurement of the ***waist circumference*** also may be useful ● Auscultation of **carotid, abdominal, and femoral bruits** ● Palpation of the **thyroid gland** ● Thorough examination of the **heart and lungs** ● Examination of the **abdomen for enlarged kidney masses, and abnormal aortic pulsation.** ● Palpation of the **lower extremities for edema and pulses** ● **Neurological** assessment

Answer 58

**Renal**: microscopic urinalysis, albumin excretion, serum BUN and/or creatinine **Endocrine**: serum Na, K, Ca, TSH **Metabolic**: fasting blood glucose, total cholesterol, HDL and LDL (often computed), TAGs Other: hematocrit, electrocardiogram

Answer 59

■ **Renovascular disease** — angiotensin-converting enzyme inhibitor radionuclide renal scan, renal duplex Doppler flow studies, and MRI angiography ■ **Pheochromocytoma** — 24-hour urine assay for creatinine, metanephrines, and catecholamines ■ **Cushing’s syndrome** — overnight dexamethasone suppression test or 24-hour urine cortisol & creatinine ■ **Primary aldosteronism** — plasma aldosterone:renin ratio

Answer 60

Encephalopathy Myocardial infarction Unstable angina Pulmonary edema Eclampsia Stroke Head trauma Life-threatening arterial bleeding Aortic dissection

Answer 61

● For the general patient population **with hypertension**, the ***BP goal is <140 / 90 mmHg*** (associated with a decrease in cardiovascular disease (CVD) complications ● Lower BP goals for patients at **higher risk of CVD:** patients with hypertension and diabetes or renal disease, the ***BP goal is <130 / 80 mmHg.***

Answer 62

● General measures instituted ○ Relief of stress ○ Dietary management ○ Regular aerobic exercise ○ Weight reduction (if needed) ○ Control of other risk factors contributing to the development of arteriosclerosis ● Lifestyle modifications

Answer 63

1. Weight reduction 2. Adopt DASH eating plan 3. Dietary sodium reduction 4. Physical activity 5. Moderation of alcohol consumption

Answer 64

Maintain normal bod wt (BMI 18.5-24.9kg/m2) (<25kg/m2) Approximate SBP Reduction: 5-20mmHg/10 kg wt loss

Answer 65

Diet rich in fruits, veggies, and low-fat dairy products with a reduced content of saturated and total fat. Approximate SBP Reduction: 8-14 mmHg

Answer 66

Reduce Na to no more than 100mmol per day (2.4g NaCl) (<6g/day) Approximate SBP Reduction: 2-8 mmHg

Answer 67

Regular aerobic physical activity s/a brisk walking (at least 30 mins per day, most days of the week) Approximate SBP Reduction: 4-9 mmHg

Answer 68

Limit consumption to no more than 2 drinks (1 oz or 30mL ethanol; e.g., 24 oz beer, 10 oz wine, or 3 oz 80-proof whiskey) per day in most men and to no more than 1 drink per day in women and lighter weight persons. Approximate SBP Reduction: 2-4 mmHg

Answer 69

● Aim of drug therapy — to use a drug alone or in combination, to return arterial pressure to normal levels with minimal side effects

Answer 70

Diuretic BB ACE inhibitor Angiotensin receptor blocker (ARB) Aldo ANT

Answer 71

BB ACE inhi Aldo ANT

Answer 72

Diuretic BB ACE inhibitors CCB

Answer 73

Diuretic BB ACE inhi ARB CCB

Answer 74

ACE inhi ARB

Answer 75

Diuretic ACE inhi

Answer 76

Ischemic heart disease (IHD)

Answer 77

BB; alternatively, long-acting CCBs can be used.

Answer 78

BBs and ACEls, with addition of other drugs as needed for BP control.

Answer 79

ACEls, BBs, and aldosterone antagonists Intensive lipid management and aspirin therapy are also indicated

Answer 80

HF (heart failure)

Answer 81

Fastidious BP and cholesterol control

Answer 82

ACEls and BBs

Answer 83

ACEls, BBs, ARBs, and aldosterone blockers

Answer 84

○ Combinations of two or more drugs are usually needed to achieve the **target goal of <130 / 80 mmHg.** ○ **Thiazide diuretics, BBs, ACEls, ARBs, and CCBs** are beneficial in ***reducing CVD and stroke incidence in patients with diabetes.*** ○ **ACEl — or ARB- based treatments** favorably ***affect the progression of diabetic nephropathy and reduce albuminuria***; and **ARBs** have been shown to ***reduce progression to macroalbuminuria***

Answer 85

■ reduced excretory function with an estimated GFR below 60 ml/min per 1.73 m2 ● corresponding approximately to a creatinine of >1.5 mg/dL in men or >1.3 mg/dL in women ■ the presence of albuminuria ● >300 mg/day or 200 mg albumin/g creatinine)

Answer 86

those with Chronic Kidney Disease

Answer 87

diabetic and nondiabetic renal disease

Answer 88

○ A limited rise in the **serum creatinine** of as much as 35 percent above baseline with ***ACEls or ARBs*** is acceptable and is not a reason to withhold treatment ***unless hyperkalemia develops.*** ○ With **advanced renal disease** (estimated GFR <30ml/min 1.73 m2, corresponding to a serum creatinine of 2.5-3 mg / dL), ***increasing doses of loop diuretics*** are usually needed in combination with other drug classes

Answer 89

○ The risks and benefits of acute lowering of BP during an acute stroke are still unclear; control of BP at intermediate levels (approximately 160/100 mmHg) is appropriate until the condition has stabilized or improved. ○ Recurrent stroke rates are lowered by the combination of an **ACEI and thiazide-type diuretic.**

Answer 90

**1. Improper BP measurement** **2. Volume overload and pseudotolerance** a. Excess sodium intake b. Volume retention from kidney disease c. Inadequate diuretic therapy **3. Drug-induced or other causes** a. Nonadherence b. Inadequate doses c. Inappropriate combinations d. Nonsteroidal anti-inflammatory drugs; cyclooxygenase 2 inhibitors e. Cocaine, amphetamines, other illicit drugs f. Sympathomimetics (decongestants, anorectics) g. Oral contraceptives h. Adrenal steroids i. Cyclosporine and tacrolimus j. Erythropoietin k. Licorice (including some chewing tobacco) l. Selected over the counter dietary supplements and medicine (e.g. ephedra, ma huang, bitter orange) **4. Associated conditions** a. Obesity b. Excess alcohol intake

Answer 91

● Age ○ The younger the patient is first noted, the greater is the reduction in life expectancy if the hypertension is left untreated ● Race ○ Urban blacks have about twice the prevalence of hypertension as whites and more than four times the ______ morbidity rate. ● Sex ○ At all ages, females with hypertension fare better than males up to the age of 65. ○ prevalence of hypertension in premenopausal females is substantially less than that in age-matched males or postmenopausal women ● Smoking ● Alcohol intake ● Elevated serum cholesterol ● Glucose intolerance ○ Elevated serum cholesterol, glucose intolerance, and/or cigarette smoking significantly enhance the effect of hypertension on mortality rate regardless of age, sex, or race ● Weight ○ A gain in weight is associated with an increased frequency of hypertension in persons with normal blood pressure and weight loss in obese persons with hypertension lowers their arterial pressure

Answer 92

1. Black Race 2. Youth 3. Male sex 4. Persistent diastolic pressure >115 mmHg 5. Smoking 6. Diabetes mellitus 7. Hypercholesterolemia 8. Obesity 9. Excess alcohol intake 10. Evidence of end organ damage a. Cardiac i. Cardiac enlargement ii. Electrocardiographic signs of ischemia or left ventricular strain iii. Myocardial infarction iv. Congestive heart failure b. Eyes i. Retinal exudates and hemorrhages ii. Papilledema c. Renal: Impaired Renal Function d. Nervous system: Cerebrovascular accident

Answer 93

NaCl > directed toward reducing extracellular fluid volume by decreasing total — body NaCl content

Answer 94

Acetazolamide Dichlorphenamide Methazolamide

Answer 95

table 29-1

Answer 96

Furosamide Bumetanide Ethacrynic acid Torsemide Azosemide Muzolimine Piretanide Tripamide

Answer 97

Glycerin Isosorbide Mannitol Urea

Answer 98

Acetazolamide

Answer 99

● Potently inhibits both the **membrane-bound and cytoplasmic forms of carbonic anhydrase,** resulting in ***nearly complete abolition of NaHCOs reabsorption in the proximal tubule.*** ● A high percentage of enzyme activity must be inhibited before an effect on electrolyte excretion is observed. ● The ***major site of action*** is the **proximal tubule** while the **collecting duct system** is the ***2° site of action*** ● **Carbonic anhydrase** is also involved in the secretion of titratable acid in the collecting duct system (a process that involves a proton pump) ● Proximal tubular epithelial cells are richly endowed with the **zinc metalloenzyme carbonic anhydrase,** which is found in the ***luminal and basolateral membranes type IV carbonic anhydrase***, an enzyme tethered to the membrane by a glycosyl phosphatidylinositol linkage) as well as in the cytoplasm (type Il carbonic anhydrase) ● The actual reaction catalyzed by carbonic anhydrase is OH + CO2 <-> HCO3; however, H2O <-> OH + H and HCO3 + H <-> H2CO3, so that the net reaction is H2O + CO2 <-> H2CO3.

Answer 100

**Effects in Urinary Excretion** ● ***Rapid rise in urinary HCO3 excretion*** to approximately 35% of filtered load. ● Increase in urinary ***pH to approximately 8*** and the development of metabolic acidosis. ● Increase excretion of K+ and phosphate but have little or no effect on the excretion of Ca2+ or Mg2+. **Effects on Renal Hemodynamics** ● Increase delivery of solutes to the macula densa triggers tubuloglomerular feedback (TGF) → increase arteriolar resistance and reduction in renal blood flow (RBF) and glomerular filtration rate (GFR). **Other Actions** ● ***Decreases the rate of formation of aqueous humor*** and consequently reduces intraocular pressure. ● ***CNS effects:*** anticonvulsant action; somnolence, paresthesias ● ***Increase CO levels in expired gas.*** ● Reduce gastric acid secretion (large doses)- no therapeutic applications. ○ Carbonic anhydrase is present in a number of extrarenal tissues including the eye, gastric mucosa, pancreas, CNS, and RBCs. ○ Carbonic anhydrase in the ciliary processes of the eye mediates the formation of large amounts of HCO3 in aqueous humor.

Answer 101

These agents are avidly bound by **carbonic anhydrase** and tissues rich in this enzyme will have higher concentrations of these agents following systemic administration.

Answer 102

● Serious toxic reactions are infrequent. ● These drugs are sulfonamide derivatives ○ may cause bone marrow depression, skin toxicity, sulfonamide-like renal lesions and allergic reactions in patients hyper-sensitive to sulfonamide.

Answer 103

1. **Patients with hepatic cirrhosis** — diversion of ammonia of renal origin from urine into the systemic circulation may induce hepatic encephalopathy. 2. **Patients with hyperchloremic acidosis** or **severe chronic obstructive pulmonary disease.**

Answer 104

● **Open-angle glaucoma** — major indication ● Secondary glaucoma and preoperatively in acute angle-closure glaucoma to lower ocular pressure before surgery. ● Treatment of ***epilepsy*** — Acetazolamide ● Symptomatic relief in patients with ***acute mountain sickness.*** ● ***Familial periodic paralysis*** ● ***Correcting a metabolic alkalosis***, especially an alkalosis caused by diuretics-induced increases in H' excretion.

Answer 105

Osmotic Diuretics

Answer 106

● By extracting water from intracellular compartments, these agents **expand the extracellular fluid volume, decrease blood viscosity, and inhibit renin release.** ● These ***effects increase renal blood flow (RBF), and the increase in renal medullary blood flow removes NaCl and urea from the renal medulla, reducing medullary tonicity.*** ● Sites of action : ○ Loop of Henle - 1° site of action ○ Proximal tubule

Answer 107

**Effects of Urinary Excretion** ● Increase urinary excretion of nearly all electrolytes, including Na+, K+, Ca2+, Mg2+,Cl-, and HCO3-. **Effects on Renal Hemodynamics** ● Increases renal blood flow (RBF) by a variety of mechanisms. ○ **Dilatation of the afferent arteriole** ***increases the hydrostatic pressure in the glomerular capillaries (PGC)*** and **dilute the plasma** which ***decreases the mean colloidal osmotic pressure in the glomerular capillaries (TTGC)*** ● **Increase pressure** in the ***proximal tubule (PT).***

Answer 108

**Glycerin and Isosorbide** can be given ***orally***, whereas **MANNITOL and UREA** must be administered ***intravenously***

Answer 109

1. **Frank pulmonary edema** — in patients with heart failure or pulmonary congestion 2. **Hyponatremia** — due to extraction of water from intracellular compartment 3. **Hypernatremia** — due to loss of water in excess of electrolytes. ● Common adverse effects — headache, nausea, vomiting

Answer 110

1. **Anuria patients** due to severe renal damage 2. Patients with **impaired liver function** —UREA 3. Patients with **active cranial bleeding** —MANNITOL and UREA

Answer 111

1. **Jaundiced patients undergoing surgery** —MANNITOL 2. Treatment of **dialysis disequilibrium syndrome** — MANNITOL 3. To **control intraocular pressure** during acute attacks of glaucoma and for short-term reductions in intraocular pressure, both preoperatively and postoperatively. 4. To **reduce cerebral edema and brain mass** before and after neurosurgery — MANNITOL

Answer 112

Inhibitors of Na+ - K+ - 2CI- Symport (Loop Diuretics; High-Ceiling Diuretics)

Answer 113

1. Approximately 25% of the filtered Na Load normally is ***reabsorbed by the thick ascending limb.*** 2. **Nephron segments past the thick ascending** limb ***do not*** possess the reabsorption capacity to rescue the flood of rejects exiting the thick ascending limb. Refer to Table 29-4.

Answer 114

FUROSEMIDE, BUMETANIDE, AZOSEMIDE, PIRETANIDE, and TRIPAMIDE

Answer 115

ETHACRYNIC ACID

Answer 116

● **Bind to the Na+ - K+ - 2Cl- symporter in the thick ascending limb** and block its function, bringing salt transport in this segment of the nephron to a virtual standstill. ● Also **inhibit Ca2+ and Mg2+ reabsorption in the thick ascending limb** by abolishing the transepithelial potential difference that is the dominant driving force for reabsorption of these cations. ● The ***primary site of action*** is the thick ascending limb. ● In the thick ascending limb, flux of Na+, K+, and Cl- from the lumen into the epithelial cell is mediated by a Na+ - K+ - 2Cl- symporter. This symporter captures the free energy in the Na+ electrochemical gradient established by the basolateral Na+ pump and provide for “uphill” transport of K+ and Cl- into the cell. ○ K+ channels in the luminal membrane (called **ROMK**) provide a ***conductive pathway for the apical recycling of this cation*** and basolateral Cl- channels (called **CLCN**) provide a ***basolateral exit mechanism for CI-*** ● The luminal membranes of epithelial cells in the **thick ascending limb** have conductive pathways (channels) only for K+. Therefore the **apical membrane voltage** is determined by the ***equilibrium potential for K+.*** ● The basolateral membrane has channels for both K and Cl, so that the basolateral membrane voltage is less than Ek; i.e., conductance for CI- depolarizes the basolateral membrane.

Answer 117

**Effects on Urinary Excretion** ● Profound increase in the urinary excretion of ***Na+ and CI-*** ● Increase excretion of ***Ca2+ and Mg2+*** ● Some (***FUROSEMIDE***) have ***weak carbonic anhydrase-inhibiting activity*** → increase urinary excretion of HCO3 and phosphate. ● All increase the urinary excretion of K+ and titratable acid. ○ This effect is due in part to increased delivery of Na+ to the distal tubule. ● **Acutely**, these agents ***increase the excretion of uric acid*** whereas **chronic administration** results in ***reduced excretion of uric acid.*** ● ***Block the kidney's ability to concentrate urine during hydropenia.*** ● ***Impair the kidney’s ability to excrete a dilute urine during water diuresis.*** **Effects on Renal Hemodynamics** ● ***Increase total renal blood flow (RBF)*** and redistribute RBF to the mid cortex. ● ***Block tubuloglomerular feedback (TGF)*** by inhibiting salt transport into the macula densa, so that the macula densa no longer can “sense” NaCl concentrations in the tubular fluid ● Powerful stimulators of ***renin*** release. Other Actions ● ***Direct vascular effects*** ○ **Furosemide** acutely increases systemic venous capacitance and thereby decreases left ventricular filling pressure. ● ***Inhibit electrolyte transport in many tissues*** — this effect is clinically important only in the **inner ear**, where alterations in the electrolyte composition of endolymph may contribute to drug-induced ototoxicity.

Answer 118

● FUROSEMIDE, BUMETANIDE, ETHACRYNIC ACID, TORSEMIDE are extensively found in ***plasma proteins.*** ● TORSEMIDE has a ***longer half-life*** than the other drugs

Answer 119

● Most adverse effects are due to abnormalities of fluid and electrolyte balance. ○ Serious depletion of total body Na+ → hyponatremia and/or extracellular fluid volume depletion associated with hypotension, reduced glomerular filtration rate (GFR), circulatory collapse, thromboembolic episodes, and hepatic encephalopathy (patients with liver disease) ○ Increase urinary excretion of K+ and H+ → hypochloremic alkalosis. ○ Hypokalemia → induce cardiac arrhythmias particularly in patients taking cardiac glycosides ○ Increase Mg2+ and Ca2+ excretion → hypomagnesemia and hypocalcemia ● Ototoxicity — tinnitus, hearing impairment, deafness, vertigo and sense of fullness in the ears. ● Hyperuricemia and hyperglycemia ● Increase plasma levels of LDL cholesterol and triglycerides. ● Decrease plasma levels of HDL cholesterol

Answer 120

1. Severe Na+ and volume depletion 2. Hypersensitivity to sulfonamide 3. Anuria unresponsive to a trial dose of loop diuretic

Answer 121

1. Treatment of acute pulmonary edema - major use 2. Chronic congestive heart failure 3. Hypertension 4. Edema of nephrotic syndrome 5. Edema and ascites of liver cirrhosis. 6. Edema associated with chronic renal insufficiency. 7. Drug overdose — to induce a forced diuresis to facilitate more rapid renal elimination of the offending drug. 8. Hypercalcemia 9. Life-threatening hyponatremia

Answer 122

Bendroflumethiazide Chlorothiazide Hydrochlorothiazide Hydroflumethiazide Methychlothiazide Polythiazide Trichlormethiazide Chlorthalidone Indapamide Metolazone Quinethazone

Answer 123

Amiloride Triamterene

Answer 124

Spironolactone Canrenone Potassium canrenoate

Answer 125

● Inhibit the Na - CI Symporter perhaps by competing for the CI binding site. ● Sites of action: ○ Distal convoluted tubule (DCT) - **1°** site of action ○ Proximal tubule - **2°** site of action ● As with the other nephron segments, transport is powered by a Na+ pump in the basolateral membrane. ● The free energy in the electrochemical gradient for Na+ is harnessed by a Na+ - CI symporter, in the luminal membrane, which moves CI into the epithelial cell against its electrochemical gradient. Cl- then passively exits the basolateral membrane via CI channel.

Answer 126

**Effects on Urinary Excretion** ● Inhibit NaCl transport in the DCT → increase ***Na+ and Cl- excretion.*** ● ***Increase HCO3- and phosphate excretion*** → these agents have weak inhibitors of carbonic anhydrase ● ***Increase excretion of K+ and titratable acid*** → due to increased delivery of Na+ to the distal tubule. ● **Increase** uric acid excretion → **acute** administration. ● **Reduced** uric acid excretion → **chronic** administration ● ***Decrease Ca2+ excretion*** → **chronic** administration ● ***Mild magnesuria*** ● Alter the ability of the kidney to excrete a dilute urine during water diuresis. **Effects on Renal Hemodynamics** ● Variably ***reduce*** glomerular filtration rate (GFR) due to **increases in intratubular pressure.** ● Do not affect the renal blood flow (RBF). ● Little or no influence on tubuloglomerular feedback (TGF). Other Actions ● Inhibit phosphodiesterase, mitochondrial oxygen consumption, and renal uptake of fatty acids — no clinical significance

Answer 127

Probenecid

Answer 128

● Sexual dysfunction (erection problems) ● Most serious adverse effects are related to abnormalities of fluid and electrolyte balance. ○ Extracellular volume depletion ○ Hypotension ○ Hypokalemia, hyponatremia, hypochloremia, hypomagnesemia ○ metabolic alkalosis ○ hypercalcemia, hyperuricemia ● Decrease glucose tolerance ● Increase plasma levels of LDL cholesterol, total cholesterol, and total triglycerides.

Answer 129

Hypersensitivity to sulfonamide

Answer 130

1. Congestive heart failure 2. Treatment of edema associated with hepatic cirrhosis, nephritic syndrome, chronic renal failure, acute glomerulonephritis ● Most thiazide diuretics are ineffective when the glomerular filtration rate (GFR) is <30 — 40 ml/min. — exceptions are METOLAZONE and INDAPAMIDE 3. Calcium nephrolithiasis and osteoporosis - these agents reduce urinary excretion of Ca2+ 4. Nephrogenic diabetes insipidus 5. Management of Br- intoxication

Answer 131

AMILORIDE Inhibitors of Renal Epithelial Na+ channels (K+ -Sparing Diuretics)

Answer 132

TRIAMTERENE

Answer 133

AMILORIDE AND TRIAMTERENE

Answer 134

● Blockade of Na+ channels in the luminal membrane of principal cells in the late distal tubule and collecting duct. ● Sites of action: ○ Late distal tubule ○ Collecting duct ● **Principal cells** in the late distal tubule and collecting duct have in their luminal membranes a **Na+ channel** that provide a conductive pathway for the entry of Na+ into the cell down the electrochemical gradient created by the basolateral Na+ pump. ● The higher permeability of the luminal membrane for Na+ depolarizes the luminal membrane, but not the basolateral membrane, creating a lumen-negative transepithelial potential difference. ● This transepithelial voltage provides an important ***driving force for the secretion of K+*** into the lumen via **K+ channels (ROMK)** in the luminal membrane.

Answer 135

**Effects on Urinary Excretion** ● Mild increase in the excretion rates of Na+ and СГ ● Decrease the excretion rates of K+, H+, Ca2+ and Mg2+ ● Decrease uric acid excretion - chronic administration **Effects on Renal Hemodynamics** ● Little or no effect on renal hemodynamics ● Do not alter tubuloglomerular feedback (TGF) Other Actions ● Blocks the Na+ - H+ and Na+ - Ca2+ antiporters ● Inhibit Na+ pump

Answer 136

Triamterene

Answer 137

● Hyperkalemia - most dangerous adverse effect ● Triamterene - reduce glucose tolerance, induce photosensitization, interstitial nephritis, renal stone. ○ most common are nausea, vomiting, leg cramps, dizziness ● Amiloride - most common are nausea, vomiting, diarrhea, and head-ache.

Answer 138

1. Patients with hyperkalemia 2. Patients at risk of developing hyperkalemia (patients with renal failure, receiving other K+ - sparing diuretics, taking ACE inhibitors, or K+ supplements)

Answer 139

**1. Treatment of edema and hypertension** ● Seldom used as sole agents in these conditions but in combination with other diuretics. ● Coadministration of a Na+- channel inhibitor augments the diuretic and antihypertensive response to thiazide or loop diuretics and tends to result in normal values of plasma K+ **2. Liddle syndrome** **3. Cystic fibrosis** - aerosolized AMILORIDE improves mucociliary clearance and augments hydration of respiratory secretions. **4. Lithium-induced nephrogenic diabetes insipidus - AMILORIDE**

Answer 140

Mineralocorticoids

Answer 141

● Competitively inhibit the binding of aldosterone to the mineralocorticoid receptor (MR). ● **Epithelial cells** in the late distal tubule and collecting duct containing cytoplasmic MRs that have a high affinity for aldosterone. This receptor is a member of the superfamily of receptors for steroid hormones, thyroid hormones, vitamin D, and retinoids. ● **Aldosterone** enters the epithelial cells from the basolateral membrane and binds to MRs; ● The **MR - aldosterone complex** translocates to the nucleus, where it binds to specific sequences of **DNA** (hormone-responsive elements) and thereby regulates the expression of multiple gene products called aldosterone—induced proteins (AlPs) which have the following effects: ○ activation of “silent” Na+ channels and “silent” Na+ pumps that preexist in the cell membrane; ○ alterations in the cycling of Na+ channels and Na+ pumps between the cytosol and cell membrane so that more channels and pumps are located in the membrane; ○ increase expression of Na+ channels and Na+ pumps; ○ changes in the permeability of the tight junctions; and increased activity of enzymes in the mitochondria that are involved in ATP production. ● The net effect of **aldosterone-induced proteins** (AIPs) is to ***increase Na+ conductance of the luminal membrane and sodium pump activity of the basolateral membrane*** → transepithelial NaCl transport is enhanced and the lumen-negative transepithelial voltage is increased. ● The MR - spironolactone complex is **not** able to induce the synthesis of AlPs

Answer 142

**Effects on Urinary Excretion** ● Effects of **SPIRONOLACTONE** on urinary excretion are very similar to those induced by renal epithelial Na+ - channel inhibitors. ● The clinical efficacy of this drug is a function of **endogenous levels of aldosterone.** ○ The higher the levels of endogenous aldosterone, the greater the effects of this drug on urinary excretion. **Effects on Renal Hemodynamics** ● Little or no effect on renal hemodynamics ● Does not alter TGF. Other Actions ● High concentrations of **SPIRONOLACTONE** interfere with steroid biosynthesis by ***inhibiting 11B- and 18-, 21-, and 17a- hydroxylase*** — have limited clinical relevance.

Answer 143

Spironolactone

Answer 144

Canrenoate

Answer 145

MR antagonists

Answer 146

● **Life—threatening hyperkalemia** ● Induce **metabolic acidosis in cirrhotic patients** ● **Gynecomastia, impotence, decreased libido, hirsutism, deepening of the voice, and menstrual irregularities** — due to its steroid structure ● **Diarrhea, gastritis, gastric bleeding, and peptic ulcer** ● **CNS adverse effects** — drowsiness, lethargy, ataxia, confusion, and headache ● **Skin rashes**

Answer 147

1. Patients with **hyperkalemia** and patients at **increased risk** of developing hyperkalemia 2. Patients with **peptic ulcers**

Answer 148

1. Coadministered with thiazide or loop diuretics in the treatment of edema and Hypertension 2. Primary hyperaldosteronism —**SPIRONOLACTONE** 3. Refractory edema associated with 2° aldosteronism 4. Hepatic cirrhosis — **SPIRONOLACTONE is the diuretic of choice**

Answer 149

● **ACE inhibitors** are specific competitive inhibitors of peptidyl dipeptidase, the enzyme that converts angiotensin I to angiotensin II. ○ **Angiotensin Il** is a ***potent direct vasoconstrictor*** — these drugs inhibit vasoconstriction. ○ Angiotensin Il ***stimulates the secretion of aldosterone***, which promotes **salt and water retention** — these ***drugs inhibit salt and water retention and slightly increase serum K+ levels.*** ● Because **peptidyl dipeptidase** is necessary to catalyze the ***degradation of bradykinin***, the ACE inhibitors may increase the concentration of bradykinin, which is a ***potent vasodilator.***

Answer 150

● Attenuate or abolish responses to **angiotensin I** but not to angiotensin Il ● **Increase bradykinin** levels ● Increase by fivefold the circulating levels of the **natural stem-cell N-acetyl-seryl-aspartyl-lysyl-proline** ● Interfere with both **short- and long-loop negative feedbacks on renin release** — increase ***renin release and the rate of formation of angiotensin I***.

Answer 151

● **Reduce afterload and systolic wall stress** → ***↑cardiac output and cardiac index*** ● **Decrease heart rate** ● **Decrease systemic blood pressure** ● **Decrease renovascular resistance** — ***increase renal blood flow*** ● **Reduced stimulus to secretion of aldosterone by angiotensin I** — ***natriuresis*** ● **Reduction of pulmonary arterial pressure**, pulmonary capillary wedge pressure, and left atrial and left ventricular filling volumes and pressures — ***diminish preload and diastolic wall stress.*** Figure 31-4 page 14

Answer 152

- Captopril - Enalapril - Benazepril - Fosinopril - Trandolapril - Quinapril - Ramipril - Moexipril - Perindopril

Answer 153

○ Rapidly absorbed when given orally and has a bioavailability of about **75%** ○ Half-life of approximately **2 hours.** ○ ***Eliminated in urine, 40-50% as captopril,*** and ***the rest as captopril disulfide dimers and captopril-cysteine disulfide.*** ○ Oral dosage ■ **6.25-50 mg 2-3x daily** ■ **25 mg BID** — for initiation of therapy for heart failure and hypertension ○ ***Food reduces the oral bioavailability of this drug by 25-30%***, this drug should be given **one hour before meals**

Answer 154

○ Rapidly absorbed when given orally and has an **oral bioavailability of about 60% (not reduced by food).** ○ Half-life of only **1.3 hours.** ○ Nearly all of the drug is ***eliminated by the kidneys either as intact enalapril or enalaprilat*** ○ Oral dosage ■ **2.5-40 mg daily** (single or divided dosage) ■ **2.5 mg and 5 mg daily** — for ***initiation of therapy for heart failure and hypertension*** ■ **2.5 mg daily** — ***initial dose for hypertensive*** patients who are taking ***diuretics, are water — or Na+ - depleted, or have heart failure***

Answer 155

Lisinopril

Answer 156

○ ***Slowly, variably, and incompletely (about 30%) absorbed after oral administration (not reduced by food).*** ○ Plasma half-life is about **12 hours.** ○ Does **not** accumulate in tissues. ○ Oral dosage ■ **5-40 mg daily** (single or divided dosage) ■ **5 mg and 10 mg daily** — ***initiation therapy for heart failure and hypertension*** ■ **2.5 mg** — recommended for patients with ***heart failure who are hyponatremic or have renal impairment.***

Answer 157

○ Cleavage of the ester moiety by hepatic esterases transforms **benazepril hydrochloride**, a prodrug, into **Benazeprilat** ○ ***Rapidly, yet incompletely (37%), absorbed after oral administration (only slightly reduced by food).*** ○ Nearly completely metabolized to Benazeprilat and to the glucuronide conjugates of benazepril and benazeprilat, which are excreted into both the urine and bile. ○ Effective half-life in plasma is about **10-11 hours** ○ With the exception of the lungs, it does not accumulate in tissues. ○ Oral dosage — **5-80 mg daily** (single or divided dosage)

Answer 158

○ Cleavage of the ester moiety by hepatic esterases transforms **fosinopril**, a prodrug, into **FOSINOPRILAT** ○ ***Slowly and incompletely (36%) absorbed after oral administration (rate but not extent reduced by food) early completely metabolized to fosinopril (75%) and to the glucuronide conjugate of fosinoprilat.*** ○ These are excreted in both the urine and bile. ○ Effective half-life in plasma is about **11.5 hours,** and its clearance is not significantly altered by renal impairment. ○ Oral dosage ■ **10-80 mg daily** (single or divided dosage) ■ **5 mg daily** — in patients with Na+ or water depletion or renal failure.

Answer 159

○ Approximately 10% and 70% of an oral dose is bioavailable (absorption rate but not extent is reduced by food as trandolapril and trandolaprilat) ○ ***Trandolaprilat*** is about **8x more potent** than trandolapril as an ACE inhibitor. ○ Metabolized to trandolapril and to inactive metabolites and these are recovered in the **urine (33%, mostly trandolapril)** and **feces (66%)** ○ Trandolaprilat displays biphasic elimination kinetics with an ***initial half-life of about 10 hours (the major component of elimination)***, followed by a more prolonged half-life due to slow dissociation of trandolapril from tissue ACE. ○ Oral dosage ■ **1-8 mg daily** (single or divided dosage) ■ **0.5 mg** — initial dose in patients who are taking diuretics or who have renal impairment.

Answer 160

○ Cleavage of the ester moiety by hepatic esterases transforms **quinapril hydrochloride**, a prodrug, into ***QUINAPRILAT*** ○ ***Rapidly absorbed (peak concentrations are achieved in 1 hour, but the peak may be delayed after food), and its rate but not extent of oral absorption (60%) may be reduced by food.*** ○ Metabolized to quinaprilat and to other minor metabolites and quinaprilat is excreted in the **urine (61%) and feces (37%)** ○ Initial half-life of quinaprilat is about **2 hours**; a prolonged terminal half-life of about **25 hours** may be due to high - affinity binding of the drug to tissue ACE. ○ Oral dosage — **5-80 mg daily** (single or divided dosage)

Answer 161

○ Cleavage of the ester moiety by hepatic esterases transforms ramipril into RAMIPRILAT ○ Rapidly absorbed and the rate but not the extent of its oral absorption (50-80%) is reduced by food. ○ Metabolized to ramiprilat and to inactive metabolites and these are excreted predominantly by the kidneys. ○ Ramiprilat displays triphasic elimination kinetics with half-lives of **2-4 hours, 9-18 hours, and greater than 50 hours.** ○ This triphasic elimination is due to extensive distribution to all tissues (initial half-life), clearance of free ramiprilat from plasma (intermediate half-life), and dissociation from tissue ACE (terminal half-life) ○ Oral dosage — **1.25-20 mg daily** (single or divided dosage)

Answer 162

○ **Incompletely absorbed**, with bioavailability as moexipril of about ***13%.*** ○ Bioavailability is markedly decreased by food, so it should be taken one hour before meals. ○ Elimination half-life varies between **2-12 hours.** ○ Oral dosage — **7.5-30 mg daily in one or two divided doses.** ○ Dosage range is **halved** in patients who are taking ***diuretics or who have renal impairment.***

Answer 163

○ A prodrug and 30-50% of systemically available perindopril is transformed to PERINDOPRILAT by hepatic esterases. ○ Oral bioavailability of perindopril (75%) is not affected by food but perindoprilat's bioavailability is reduced by approximately 35% ○ Metabolized to perindoprilat and to inactive metabolites and these are excreted predominantly by the kidneys. ○ Perindoprilat displays biphasic elimination kinetics with half-lives of **3-10 hours** ( the major component of elimination) and **30-120 hours** (due to slow dissociation of perindoprilat from tissue ACE) ○ Oral dosage — **2-16 mg daily (single or divided dosage)**

Answer 164

**1. Hypertension** ● Lower blood pressure except when high blood pressure is due to ***primary aldosteronism.*** ● Inhibition of ACE lowers systemic vascular resistance and mean, diastolic, and systolic blood pressures in various dysfunction. **2. Left ventricular systolic dysfunction** ● These drugs should be given to all patients with impaired left ventricular systolic function whether or not they are experiencing symptoms of overt heart failure. **3. Acute myocardial infarction** ● These agents reduce overall mortality when treatment is begun during the ***periinfarction period.*** ● Unless contraindicated (eg. cardiogenic shock or severe hypotension), these agents should be started immediately during the acute phase of MI and can be administered along with thrombolytics, aspirin, and B-adrenergic receptor antagonists. **4. Patients who are at high risk of cardiovascular events** ● These agents tilt the fibrinolytic balance toward a profibrinolytic state by reducing plasma levels of plasminogen activator inhibitor - 1 and improve the endothelial vasomotor dysfunction in patients with coronary artery disease. **5. Chronic renal failure** ● These agents prevents or delay the progression of renal disease in patients with ***type I diabetes mellitus and diabetic nephropathy*** ● May decrease retinopathy progression in **type I diabetics*** **6. Scleroderma renal crisis**

Answer 165

**1. Hypotension** ○ A steep fall in blood pressure may occur following the first dose of an ACE inhibitor in patients with elevated PRA (plasma renin activity) ○ Treatment should be initiated with very small doses of these agents, or salt intake should be increased and diuretics withdrawn before beginning therapy. **2. Cough** ○ Induce a bothersome, dry cough in 5-20% of patients. ○ Usually not dose-related, occurs more frequently in women than in men. ○ Usually develops between 1 week and 6 months after initiation of therapy, and sometimes require cessation of therapy. ○ May be mediated by the accumulation in the lungs of bradykinin, substance P, and/or prostaglandins **3. Hyperkalemia** ○ Seen in patients with renal insufficiency or in patients taking K+, sparing diuretics, K supplement, B - adrenergic receptor blockers, or NSAIDs. **4. Acute renal failure** ○ Can induce acute renal insufficiency in patients with bilateral renal artery stenosis, stenosis of the artery to a single remaining kidney, heart failure, or dehydration due to diarrhea or diuretics. ○ Older patients with congestive heart failure are particularly susceptible to ACE inhibitor-induced acute renal failure. **5. Fetopathic Potential** ○ Continued administration of these agents during the 2nd and 3rd trimesters can cause oligohydramnios fetal calvarial hypoplasia, fetal pulmonary hypoplasia, fetal growth retardation, fetal death, neonatal anuria, and neonatal death. ○ A CE inhibitors are not contraindicated in women of reproductive age, once pregnancy is diagnosed, it is imperative that ACE inhibitors be discontinued as soon as possible. ○ The fetus is not at risk of ACE inhibitor-induced pathology if ACE inhibitors are discontinued during the 1% trimester of pregnancy. **6. Proteinuria** ○ Proteinuria of more than 1 gm/day ○ In general, proteinuria is not a contraindication for ACE inhibitors. **7. Angioneurotic edema** ○ Induce a rapid swelling of the nose, throat, mouth, glottis, larynx, lips, and/or tongue. ○ Not dose-related and nearly always develops within the first week of therapy, usually within the first few hours after the initial dose. ○ Mechanism is unknown, it may involve the accumulation of bradykinin, induction of tissue-specific autoantibodies, or inhibition of complement 1- esterase inactivator. ○ Disappears within hours once these agents are stopped. ○ If necessary, administer Epinephrine, an antihistamine, and/or a corticosteroid. **8. Dysgeusia** ○ Alteration in or loss of taste may occur more frequently with captopril. ○ Is reversible. **9. Neutropenia** ○ Rare but serious side effects. ○ Occurs predominantly in hypertensive patients with collagen-vascular or renal parenchymal disease **10. Glycosuria** ○ Exceedingly rare and reversible **11. Hepatotoxicity** ○ Exceedingly rare and reversible ○ Usually of the cholestatic variety.

Answer 166

● Competitively inhibits angiotensin Il at its AT1 receptor site Figure 11-4 page 13: Actions of angiotensin-converting enzyme inhibitors and AT1 receptor blockers. The enz is responsible for activating angiotensin by conversion of angiotensin I to II and for inactivating bradykinin, a vasodilator normally present in very low concentrations. Block of the enz thus decreases the conc of a vasoconstrictor and increased the conc of a vasodilator. The AT1 receptor antagonists lack the effect on bradykinin lvls, which may explain then lower incidence of cough observed with these agents.

Answer 167

**● ARBs potently and selectively inhibit, both in vitro and in vivo, most of the biological effects of angiotensin I, including angiotensin induced:** ○ Contraction of vascular smooth muscle ○ Rapid pressor responses ○ Slow pressor responses ○ Thirst ○ Vasopressin release ○ Aldosterone secretion ○ Release of adrenal catecholamines ○ Enhancement of noradrenergic neurotransmission ○ Increases in sympathetic tone ○ Changes in renal function ○ Cellular hypertrophy and hyperplasia **● ARBs differ from ACE inhibitors in several aspects:** 1. ARBs reduce activation of AT receptors more effectively than do ACE inhibitors. 2. In contrast to ACE inhibitors, ARBs indirectly activate AT, receptors by increasing angiotensin Il levels 3. ACE inhibitors may increase angiotensin (1-7) levels more than do ARBs 4. ACE inhibitors increase the levels of a number of ACE substrates, including bradykinin, and Ac-SDKP

Answer 168

● Oral bioavailability is generally low (<50%); except for Irbesartan (70%) ● Protein binding is high (>90%)

Answer 169

**CANDESARTAN CILEXETIL** ○ An ***inactive ester prodrug*** that is completely hydrolyzed to the active form, candesartan, during absorption from the GIT. ○ Plasma half-life is about **9 hours**. ○ Renal elimination (33%) and biliary excretion (67%) ○ Oral dosage — ***4-32 mg daily - OD or BID*** **EPROSARTAN** ○ Plasma half-life ranges from **11-15 hours**. ○ Cleared by renal elimination and biliary excretion ○ Plasma clearance is affected by both renal insufficiency and hepatic insufficiency ○ Oral dosage — ***400-800 mg/day - OD or BID*** **IRBESARTAN** ○ Plasma half-life ranges from **11-15 hours** ○ Cleared by ***renal elimination (20%) and biliary excretion (80%).*** ○ Plasma clearance is unaffected by either renal or mild-to-moderate hepatic insufficiency ○ Oral dosage — ***150-300 mg daily - OD*** **LOSARTAN** ○ Approximately 14% of an oral dose is converted to the ***5- carboxylic acid*** metabolite, designated **EXP3174**, which is ***more potent than losartan as an AT1 receptor antagonist.*** ○ The metabolism of losartan to **EXP3174** and to inactive metabolites is mediated by ***CYP2C9 and 3A4.*** ○ Plasma half-lives are **2.5 and 6-9 hours**, respectively. ○ Plasma clearance is affected by **hepatic** but not renal insufficiency ○ Oral dosage — **25-100 mg/day - OD or BID** **TELMISARTAN** ○ Plasma half-life is about **24 hours** ○ Cleared mainly by ciliary secretion of intact drug ○ Plasma clearance is affected by **hepatic**, but not renal insufficiency ○ Oral dosage — **40-80 mg once daily** **VALSARTAN** ○ Plasma half-life is about **9 hours** ○ **Food markedly decreases absorption.** ○ Cleared from the circulation by the liver (about 70% of total clearance) ○ Plasma clearance is affected by **hepatitis** but not renal insufficiency. ○ Oral dosage — **80-320 mg once daily**

Answer 170

1. Treatment of hypertension — the only approved therapeutic indication 2. Reserve for treatment of heart failure in patients who cannot tolerate or have an unsatisfactory response to ACE inhibitors. 3. Treatment of partial hypertension in patients with cirrhosis and portal hypertension without compromising renal function — Losartan

Answer 171

1. **Angioneurotic edema** — incidence is lesser compared to ACE inhibitors 2. **Fetopathic potential** ○ Should be discontinued before the 2nd trimester of pregnancy. 3. **Hyperkalemia** in patients with renal disease or in patients taking K+ supplement or K - sparing drugs.