B4M1C1: Cardiovascular System Flashcards
What are the layers of the artery?
IMA
Tunica Intima
Tunica Media
Tunica Adventitia/Externa
The innermost layer of the artery, tunica intima, is made up of:
- Endothelium
- Subendothelial layer
- Internal elastic membrane
What contains rodlike inclusion bodies which contain a procoagulant factor?
Weibel Palade bodies
Layer of flattened cells
Endothelium
Delicate fibroelastic tissue
Subendothelial layer
What marks the boundary between the Tunica intima and Tunica media?
Internal elastic membrane
What contains fenestrations?
Internal elastic membrane
Importance of fenestrations
Essential for the nutrition of the avascular Tunica Media
What is made up of smooth muscle and elastic fibers?
Tunica media
Fibroelastic tissue & has external elastic membrane
Tunica adventitia/externa
What marks the boundary between the Tunica media and Tunica adventitia?
External elastic membrane
What are the layers of the wall of the heart?
EME
Endocardium - innermost layer
Myocardium - middle & thickest
Epicardium - outermost
Endocardium composition:
- Endothelium
- Sub-endothelial layer
- Sub-endocardial layer
Layer of flattened cells which form a long tube
Endothelium
What contains nerves and blood vessels, fiboblasts, collagen, and elastic fibers?
Sub-endothelial layer
What is a main mass of the endocardium, fibroelastic tissue, contains nerves, blood vessels, and fat cells?
Sub-endocardial layer
What is the middle and thickest layer made up of cardiac muscles?
Myocardium
What is composed of mesothelium and areolar tissue?
Epicardium
Forms the visceral layer of the pericardium
Epicardium
● independent of nervous stimulation
● long & branching with end to end attachment (intercalated disc)
● one nucleus at main segment
● myofibrils in parallel bundles
● fainter & closer cross striations
Cardiac muscle
● specialized for conduction of impulses
● bigger but shorter, more sarcoplasm but fewer myofibrils
● cross striations are fainter
● nuclei fewer, larger & paler
Purkinje fiber
What is a serous membrane that covers the heart?
Pericardium
BP = CO x PR
What affects Cardiac Output?
Blood Volume SAM
1. Sodium
2. Mineralocorticoids
3. Atriopeptin (ANP - atrial natriuretic peptide)
Cardiac Factors HC
1. Heart rate
2. Contractility
BP = CO x PR
What affects Peripheral Resistance?
HUMORAL FACTORS
Constrictors CATLE
1. Catecholamines
2. Angiotensin II
3. Thromboxane
4. Leukotrienes
5. Endothelin
Dilators PKN
1. Prostaglandins
2. Kinins
3. NO/EDRF (nitric oxide-endothelium-derived relaxing factor)
NEURAL FACTORS
Constrictors
a-adrenergic
Dilators
B-adrenergic
LOCAL FACTORS
1. Autoregulation
2. Ionic (pH, hypoxia)
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:
level of diastolic pressure also systolic pressure, age, sex, race, and concomitant disease.
What is an elevated arterial pressure without a known cause?
Essential Hypertension (Primary or Idiopathic)
What is an elevated arterial pressure as a result of known or definable cause?
Secondary Hypertension
What has an evidence of left ventricular hypertrophy or left ventricular failure in the presence of sustained arterial systolic and diastolic hypertension?
Hypertensive Heart Disease
What has an arterial pressure that is sometimes within the hypertensive range?
Labile Hypertension (Borderline Hypertension)
What has a significant recent increase over previous hypertensive levels associated with evidence of vascular damage on funduscopic examination but without papilledema?
Accelerated Hypertension
What is extremely elevated systolic and diastolic arterial pressures, or hypertension associated with end-organ damage (papilledema, usually accompanied by retinal hemorrhage, encephalopathy, eclampsia, etc.) which must be lowered in one hour?
Malignant Hypertension
What is an uncontrolled hypertension which must be lowered in 24 hours and No end organ damage as mentioned in hypertensive emergencies?
Hypertensive crisis
falsely elevated BP seen in:
● Elderly patients with atherosclerotic brachial arteries
● White coat hypertension
● Mismatch in size of pressure cuff and
patient’s arm
Pseudohypertension
What are anxious patients who get elevated BP readings at the doctor’s clinic called?
Whitecoat Hypertension
PREVALENCE OF HYPERTENSION
INDUSTRIALIZED SOCIETIES
● 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.
Prevalence of HPN
UNITED STATES 🇺🇸
● 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
Prevalence of HPN
PHILIPPINES 🇵🇭
● Filipino adults 20 years and above with hypertension
○ 2012 - 21%
○ 2008 - 21%
○ 2003 - 16%
Prevalence of Various Forms of HPN in General Population and in Specialized Referral Clinics
Go back to notes 📝
Systolic Hypertension with Wide Pulse Pressure
- Decreased vascular compliance (arteriosclerosis)
-
Increased cardiac output FAPATH
- Fever
- Aortic regurgitation
- Patent ductus arteriosus
- Arteriovenous fistula
- Thyrotoxicosis
- Hyperkinetic heart syndrome
Secondary Causes of Systolic and Diastolic Hypertension
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
JNC 7
SBP then DBP althroughout
N: <120 / <80
Prehypertension: 120-139 / 80-89
Stage 1: 140-159 / 90-99
Stage 2: >=160 / >=100
JNC 8/AHA
look at cmap B4M1C1
What is a heterogeneous disorder, variables other than the arterial pressure modify its course?
● The probability of developing a morbid cardiovascular event with a given arterial pressure may vary as much as 20-fold depending on whether associated risks factors are present
● Most untreated adults with hypertension will develop further increase in arterial pressure with time.
Essential hypertension
What is associated with a shortening of life by 10-20 years, usually related to an acceleration of the atherosclerotic process?
Untreated hypertension
Who has a high risk of developing significant complications?
● Individuals who have relatively mild disease — i.e. without evidence of end organ damage — that is left untreated for 7-10 years
○ Nearly 30% will exhibit ________
○ More than 50% will have _________ related to the hypertension itself, such as cardiomegaly, congestive heart failure, retinopathy, a cerebrovascular accident, and/or renal insufficiency.
○ 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.
Pathogenesis of essential hypertension
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
What clearly plays a role in determining blood pressure levels, as evidenced by studies comparing blood pressure in monozygotic and dizygotic twins, studies of familial aggregation of hypertension comparing the blood pressure of biologic and adoptive siblings, and adoption studies?
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.
These lead to an adaptive increase in secretion of aldosterone, increased salt and water resorption, plasma volume expansion, and ultimately hypertension.
Gene defects in enzymes involved in aldosterone metabolism (e.g. aldosterone synthase, Il B - hydroxylase, 17 a - hydroxylase)
○ Mutations in proteins that affect sodium reabsorption.
■ For example, mutations in an epithelial sodium channel protein lead to increased distal tubular reabsorption of sodium induced by aldosterone, resulting in a moderately severe form of salt-sensitive hypertension called:
Liddle syndrome
Genesis hypothesized to be involved in essential hypertension
Table 246-3
Role of Intermediate Phenotype in Genetic Analysis
Table 246-4
ENVIRONMENTAL FACTORS
● 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.”
What is an enzyme secreted by the juxtaglomerular cell of the kidney and linked with aldosterone in a negative feedback loop?
Renin
What is the primary factor that modifies its rate of secretion?
Volume status of the individual, particularly as related to changes in dietary sodium intake.
The end product of the action of renin on its substrate is the generation of what peptide?
Angiotensin II
The response of target tissues to the peptide is uniquely determined by the
Prior dietary electrolyte intake
The sodium intake normally modulated adrenal and renal vascular responses to what?
angiotensin Il
With sodium restriction, what happens to the adrenal and renal vascular response?
Adrenal responses: enhanced
Renal vascular response: reduced
With sodium loading, what happens to the adrenal and renal vascular response?
Opposite of restriction
The range of plasma renin activities observed in hypertensive subjects compared to normotensive individuals?
Hypertensive: broader
Some hypertensive patients have been defined as having
low renin
and others as having high-renin essential hypertension
Low-Renin Essential Hypertension
● 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.
Hypothesis for the low plasma renin activity:
○ 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
High-Renin Essential Hypertension
● 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.
HORMONAL FACTORS (INSULIN RESISTANCE)
● 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.
What are more common in hypertensive than in normotensive individuals?
Both obesity and NIDDM
What are present even in lean hypertensive patients without NIDDM?
Hyperinsulinemia and insulin resistance
Hyperinsulinemia can increase arterial pressure by one or more of four mechanisms:
○ 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.
Note: Some hypertensives are termed as ________________ because of the absence of the sodium-mediated modulation of target tissue responses to angiotensin Il. Have hypertension that is salt sensitive because of a defect in the kidney’s ability to excrete sodium appropriately.
Non-modulators
EFFECTS OF HYPERTENSION IN THE HEART 💜
● 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
EFFECTS OF HYPERTENSION IN THE RETINA 👁
● Retinal changes
○ Focal spasm and progressive general narrowing arteriole
○ Papilledema or hemorrhages of the macular area producing scotomata, blurred vision, and even blindness.
EFFECTS OF HYPERTENSION IN THE CNS 🧠
● 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
EFFECTS OF HYPERTENSION IN THE KIDNEY 👶🦵
● 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
TWO FORMS OF SMALL BLOOD VESSEL DISEASE ASSOCIATED WITH HYPERTENSION
HYALINE ARTERIOSCLEROSIS
&
HYPERPLASTIC ARTERIOSCLEROSIS
● Encountered frequently in elderly patients, whether normotensive or hypertensive but is more generalized and more severe in patients with hypertension.
● Vascular lesion consists of a homogenous, pink, hyaline thickening of the walls of arterioles with loss of underlying structural detail and with narrowing of the lumen.
○ The lesions reflect leakage of plasma components across vascular endothelium and increasing extracellular matrix production by smooth muscle cells.
○ Presumably the chronic hemodynamic stress of hypertension or a metabolic stress in diabetes accentuates endothelial injury, thus resulting in leakage and hyaline deposition.
● The narrowing of the arteriolar lumens causes impairment of the blood supply to affected organs, particularly in kidneys.
● This is a major morphological characteristic of benign nephrosclerosis, in which the arteriolar narrowing causes diffuse renal ischemia and symmetric shrinking of the kidneys.
HYALINE ARTERIOSCLEROSIS
● Generally related to more acute or severe elevations of blood pressure and is therefore characteristic but not limited to malignant hypertension
● Characterized by onion-skin, concentric, laminated thickening of the walls of the arteriole with progressive narrowing of the lumens as seen light microscope
● With an electron microscope, the laminations consist of smooth muscle cells and thickened and reduplicated basement membrane.
● These hyperplastic changes are accompanied by deposits of fibrinoid and acute necrosis of the vessel wall, referred to as necrotizing arteriolitis. The arterioles in all tissues throughout the body may be affected but the favored site is the kidney
HYPERPLASTIC ARTERIOSCLEROSIS
What are the 3 objectives for the evaluation of patients with hypertension?
● 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
Major risk factors: cardiovascular
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)
Target organ damage:
Heart
🫀 left ventricular hypertrophy
🫀 angina or prior myocardial infarction
🫀 prior coronary revascularization
🫀 heart failure
Brain
🧠 stroke or transient ischemic attack
Chronic kidney disease
Retinopathy
What are identifiable causes of hypertension?
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
Medical History
● 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.
PHYSICAL EXAMINATION
● 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
What are the routine/basic laboratory tests recommended before initiating therapy/evaluation?
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
What are the special studies to screen for secondary hypertension?
■ 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
CONDITIONS NECESSITATING PROMPT REDUCTION OF BLOOD PRESSURE (HYPERTENSIVE URGENCIES AND EMERGENCIES)
Encephalopathy
Myocardial infarction
Unstable angina
Pulmonary edema
Eclampsia
Stroke
Head trauma
Life-threatening arterial bleeding
Aortic dissection
MANAGEMENT OF HYPERTENSION
● The ultimate public health goal of antihypertensive therapy is the reduction of cardiovascular and renal morbidity and mortality.
What is the BP goal of those with hypertension and of those who are at risk of CVD?
● 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.
NON-PHARMACOLOGIC MANAGEMENT
● 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
Lifestyle modification to manage hypertension:
- Weight reduction
- Adopt DASH eating plan
- Dietary sodium reduction
- Physical activity
- Moderation of alcohol consumption
Weight reduction recommendation:
Maintain normal bod wt (BMI 18.5-24.9kg/m2) (<25kg/m2)
Approximate SBP Reduction: 5-20mmHg/10 kg wt loss
DASH recommendation:
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
Dietary sodium reduction recommendation:
Reduce Na to no more than 100mmol per day (2.4g NaCl) (<6g/day)
Approximate SBP Reduction: 2-8 mmHg
Physical activity recommendation:
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
Moderation of alcohol consumption recommendation:
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
PHARMACOLOGIC MANAGEMENT FOR HYPERTENSION
What is the aim of drug therapy for hypertension?
● Aim of drug therapy — to use a drug alone or in
combination, to return arterial pressure to normal levels with minimal side effects
Guideline basis for compelling indications for individual drug classes:
Recommended Drugs for HEART FAILURE:
Diuretic
BB
ACE inhibitor
Angiotensin receptor blocker (ARB)
Aldo ANT
Guideline basis for compelling indications for individual drug classes:
Recommended Drugs for POSTMYOCARDIAL INFARCTION:
BB
ACE inhi
Aldo ANT
Guideline basis for compelling indications for individual drug classes:
Recommended Drugs for HIGH CORONARY DISEASE RISK:
Diuretic
BB
ACE inhibitors
CCB
Guideline basis for compelling indications for individual drug classes:
Recommended Drugs for DIABETES:
Diuretic
BB
ACE inhi
ARB
CCB
Guideline basis for compelling indications for individual drug classes:
Recommended Drugs for CKD:
ACE inhi
ARB
Guideline basis for compelling indications for individual drug classes:
Recommended Drugs for RECURRENT STROKE PREVENTION:
Diuretic
ACE inhi
What is the most common form of target organ damage associated with hypertension?
Ischemic heart disease (IHD)
What is the first drug of choice in patients with hypertension and stable angina pectoris?
BB;
alternatively, long-acting CCBs can be used.
In patients with acute coronary syndromes (unstable angina or myocardial infarction), hypertension should be treated initially with what?
BBs and ACEls, with addition of other drugs as needed for BP control.
What has proven to be most beneficial in patients with postmyocardial infarction?
ACEls, BBs, and aldosterone antagonists
Intensive lipid management and aspirin therapy are also indicated
In the form of systolic or diastolic ventricular dysfunction, this results primarily from systolic hypertension and IHD.
HF (heart failure)
What are the primary preventive measures for those at high risk for HF?
Fastidious BP and cholesterol control
What are recommnded in asymptomatic individuals with demonstrable ventricular dysfunction?
ACEls and BBs
What are recommended for those with symptomatic ventricular dysfunction or end-stage heart disease along with loop diuretics?
ACEls, BBs, ARBs, and aldosterone blockers
Diabetic Hypertension
○ 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
Therapeutic goals are to slow deterioration of renal function and prevent CVD in people with chronic kidney disease (CKD), as defined by either:
■ 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)
Hypertension appears in the majority of these
patients, and they should receive aggressive BP
management, often with three or more drugs to
reach target BP values of <130 / 80 mmHg.
those with Chronic Kidney Disease
ACEls and ARBs have demonstrated favorable effects on the progression of
diabetic and nondiabetic renal disease
CKD
○ 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
Cerebrovascular Dse
○ 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.
DIURETICS ON THE LATTER
What are the causes of resistant hypertension?
● reasons for poor therapeutic response in patients with hypertension
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
What are the factors that affect the prognosis of hypertension?
● 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
What are the risk factors for an adverse prognosis in hypertension?
- Black Race
- Youth
- Male sex
- Persistent diastolic pressure >115 mmHg
- Smoking
- Diabetes mellitus
- Hypercholesterolemia
- Obesity
- Excess alcohol intake
- 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
What are drugs that increase the rate of urine flow, also increase the rate of excretion of Na2+ (natriuresis) and of an accompanying anion, usually CI?
Diuretics
What is the major determinant of extracellular fluid volume, and most clinical applications of diuretics are directed toward reducing extracellular fluid volume?
NaCl
> directed toward reducing extracellular fluid volume by decreasing total — body NaCl content
These does not only alter the excretion of Na2+, but also may modify renal handling of other cations (K+, H+, Ca2+, and Mg2+), anions (CI-, HCO3-, and H2PO4-), and uric acid.
Diuretics
Tubule transport systems and sites of action of diuretics; page 7
PAGE 7
Inhibitors of Carbonic Anhydrase (page 7)
Acetazolamide
Dichlorphenamide
Methazolamide
Excretory and Renal Hemodynamic Effects of Diuretics (page 7)
table 29-1
Inhibitors of Na K Cl Symport (Loop Diuretics; High-Ceiling Diuretics) page 7
Furosamide
Bumetanide
Ethacrynic acid
Torsemide
Azosemide
Muzolimine
Piretanide
Tripamide
Osmotic Diuretics
Glycerin
Isosorbide
Mannitol
Urea
● prototype drug
● The common molecular motif of available carbonic anhydrase inhibitors is an unsubstituted sulfonamide moiety.
Acetazolamide
Mechanism and Site of Action of Acetazolamide
● 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.
Acetazolamide:
- Effects in Urinary Excretion
- Effects on Renal Hemodynamics
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.
Absorption and Elimination of Acetolamide
These agents are avidly bound by carbonic anhydrase and tissues rich in this enzyme will have higher concentrations of these agents following systemic administration.
Toxicity, Adverse Effects, Contraindications, Drug Interaction of Acetazolamide
● 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.
Contraindications of Acetozolamide
- Patients with hepatic cirrhosis — diversion of ammonia of renal origin from urine into the systemic circulation may induce hepatic encephalopathy.
- Patients with hyperchloremic acidosis or severe chronic obstructive pulmonary disease.
Therapeutic Uses of Acetozolamide
● 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.
What are agents that are freely filtered at the glomerulus, undergo limited reabsorption by the renal tubule, and are relatively inert pharmacologically?
● Administered in large enough doses to increase significantly the osmolality of plasma and tubular fluid.
● Refer to Table 29-3.
Osmotic Diuretics
Mechanism and Site of Action of
Osmotic Diuretics
● 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
Osmotic Diuretics:
- Effects of Urinary Excretion
- Effects on Renal Hemodynamics
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).
Absorption and Elimination of Osmotic Diuretics
Glycerin and Isosorbide can be given orally,
whereas MANNITOL and UREA must be administered intravenously
Toxicity, Adverse Effects, Contraindications, Drug Interaction
of Osmotic Diuretic
- Frank pulmonary edema — in patients with heart failure or pulmonary congestion
- Hyponatremia — due to extraction of water from intracellular compartment
- Hypernatremia — due to loss of water in excess of electrolytes.
● Common adverse effects — headache, nausea, vomiting
Contraindications of Osmotic Diuretics
- Anuria patients due to severe renal damage
- Patients with impaired liver function —UREA
- Patients with active cranial bleeding —MANNITOL and UREA
Therapeutic uses of Osmotic Diuretics
- Jaundiced patients undergoing surgery —MANNITOL
- Treatment of dialysis disequilibrium syndrome — MANNITOL
- To control intraocular pressure during acute attacks of glaucoma and for short-term reductions in intraocular pressure, both preoperatively and postoperatively.
- To reduce cerebral edema and brain mass before and after neurosurgery — MANNITOL
What are a group of diuretics that have in common an ability to block the Na+ - K+ - 2CI- symporter in the thick ascending limb of the loop of Henle?
Inhibitors of Na+ - K+ - 2CI- Symport
(Loop Diuretics; High-Ceiling Diuretics)
The efficacy of inhibitors of Na+ - K+ - 2CI symport in the thick ascending limb of the loop of Henle is due to a combination of 2 factors:
- Approximately 25% of the filtered Na Load normally is reabsorbed by the thick ascending limb.
- 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.
What contains a sulfonamide moiety?
FUROSEMIDE, BUMETANIDE, AZOSEMIDE,
PIRETANIDE, and TRIPAMIDE
What is a phenoxyacetic acid derivative?
ETHACRYNIC ACID
What is a sulfonylurea?
TORSEMIDE
Mechanism and Site of Action of Inhibitors of Na+ - K+ - 2CI- Symport
● 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.
Inhibitors of Na+ - K+ - 2CI- Symport
- Effects on Urinary Excretion
- Effects on Renal Hemodynamics
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.
Absorption and Elimination of Inhibitors of Na+ - K+ - 2CI- Symport
● FUROSEMIDE, BUMETANIDE, ETHACRYNIC
ACID, TORSEMIDE are extensively found in
plasma proteins.
● TORSEMIDE has a longer half-life than the
other drugs
Toxicity, Adverse Effects, Contraindications of Inhibitors of Na+ - K+ - 2CI- Symport
● 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
Contraindications of Inhibitors of Na+ - K+ - 2CI- Symport
- Severe Na+ and volume depletion
- Hypersensitivity to sulfonamide
- Anuria unresponsive to a trial dose of loop
diuretic
Therapeutic Uses of Inhibitors of Na+ - K+ - 2CI- Symport
- Treatment of acute pulmonary edema - major
use - Chronic congestive heart failure
- Hypertension
- Edema of nephrotic syndrome
- Edema and ascites of liver cirrhosis.
- Edema associated with chronic renal insufficiency.
- Drug overdose — to induce a forced diuresis to
facilitate more rapid renal elimination of the offending drug. - Hypercalcemia
- Life-threatening hyponatremia
Inhibitors of Na+ - K+ Symport (Thiazide and Thiazide-like Diuretics) Table 29-5 page 10
Bendroflumethiazide
Chlorothiazide
Hydrochlorothiazide
Hydroflumethiazide
Methychlothiazide
Polythiazide
Trichlormethiazide
Chlorthalidone
Indapamide
Metolazone
Quinethazone
Inhibitors of Renal Epithelial Na+ channels (K+-sparing Diuretics)
Amiloride
Triamterene
Mineralocorticoid receptor antagonists (aldosterone antagonists; potassium-sparing diuretics)
Spironolactone
Canrenone
Potassium canrenoate
Inhibitors of Na+ - CI’ Symport (Thiazide and Thiazide-Like Diuretics) Mechanism and Site of Action:
● 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.
Inhibitors of Na+ - CI’ Symport (Thiazide and Thiazide-Like Diuretics)
- Effect on Urinary Excretion
- Effect on Renal Hemodynamics
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
Absorption and Elimination: Inhibitors of Na+ - CI’ Symport
What can attenuate the diuretic response to thiazides by competing for transport into the proximal tubule?
Probenecid
Toxicity, Adverse Effects, Contraindications: Inhibitors of Na+ - CI’ Symport (Thiazide and Thiazide-Like Diuretics)
● 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.
Contraindication of Inhibitors of Na+ - CI’ Symport
Hypersensitivity to sulfonamide
What are the therapeutic uses of Inhibitors of Na+ - CI’ Symport?
- Congestive heart failure
- 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 - Calcium nephrolithiasis and osteoporosis - these agents reduce urinary excretion of Ca2+
- Nephrogenic diabetes insipidus
- Management of Br- intoxication
What is a pyrazinyl guanidine derivative?
AMILORIDE
Inhibitors of Renal Epithelial Na+ channels (K+ -Sparing Diuretics)
What is a pteridine?
TRIAMTERENE
What drugs are organic bases and are transported by the organic base secretory mechanism in the proximal tubule?
AMILORIDE AND TRIAMTERENE
Mechanism and Site of Action of Inhibitors of Renal Epithelial Na+ channels (K+ - Sparing Diuretics):
● 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.
Inhibitors of Renal Epithelial Na+ channels (K+ - Sparing Diuretics)
- Effects on Urinary Excretion
- Effects on Renal Hemodynamics
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
What is eliminated predominantly by urinary excretion of the intact drug?
Amiloride
What is extensively metabolized to an active metabolite, 4-hydroxytriamterene sulfate, and this metabolite is excreted in the urine?
Triamterene
Toxicity, Adverse Effects, Contraindications: Inhibitors of Renal Epithelial Na+ channels (K+ - Sparing Diuretics)
● 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.
Contraindications: Inhibitors of Renal Epithelial Na+ channels (K+ - Sparing Diuretics)
- Patients with hyperkalemia
- Patients at risk of developing hyperkalemia (patients with renal failure, receiving other K+ - sparing diuretics, taking ACE inhibitors, or K+ supplements)
Therapeutic Uses: Inhibitors of Renal Epithelial Na+ channels (K+ - Sparing Diuretics)
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
What can cause retention of salt and water and increase the excretion of K+ and H+ by binding to specific mineralocorticoid receptors (MR)?
Mineralocorticoids
Mechanism and Site of Action: Antagonists of Mineralocorticoid Receptors (Aldosterone Antagonists; K+ - Sparing Diuretics)
● 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
Antagonists of Mineralocorticoid Receptors (Aldosterone Antagonists; K+ - Sparing Diuretics)
- Effects on Urinary Excretion
- Effects on Renal Hemodynamincs
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.
What is partially ~ absorbed (approximately 65%), extensively metabolized, undergoes enterohepatic recirculation, highly protein bound, and short half-life (1.6 hours)?
Spironolactone
What is an active metabolite that has a half-life of approximately 16.5 hours, which prolongs the biological effect of spironolactone?
Canrenone
What is not active per se but is converted to canrenone in the body?
Canrenoate
What are the only diuretics that do not require access to the tubular lumen to induce a diuresis?
MR antagonists
Toxicity, Adverse Effects, Contraindications: Antagonists of Mineralocorticoid Receptors (Aldosterone Antagonists; K+ - Sparing Diuretics)
● 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
Contradications: Antagonists of Mineralocorticoid Receptors (Aldosterone Antagonists; K+ - Sparing Diuretics)
- Patients with hyperkalemia and patients at increased risk of developing hyperkalemia
- Patients with peptic ulcers
Therapeutic Uses of Antagonists of Mineralocorticoid Receptors (Aldosterone Antagonists; K+ - Sparing Diuretics)
- Coadministered with thiazide or loop diuretics in the treatment of edema and Hypertension
- Primary hyperaldosteronism —SPIRONOLACTONE
- Refractory edema associated with 2° aldosteronism
- Hepatic cirrhosis — SPIRONOLACTONE is the diuretic of choice
Mechanism of Action
of Angiotensin-Converting Enzyme (ACE) Inhibitors
● 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.
Pharmacologic Effects of Angiotensin-Converting Enzyme (ACE) Inhibitors
● 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.
Hemodynamics effect of ACE inhibitors:
● 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
What are the drugs that are inhibitors of ACE?
- Captopril
- Enalapril
- Benazepril
- Fosinopril
- Trandolapril
- Quinapril
- Ramipril
- Moexipril
- Perindopril
What is a potent ACE inhibitor with a Ki of 1.7 nM?
Captopril
Facts for CAPTOPRIL
○ 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
What is a prodrug that is not highly active and must be hydrolyzed by esterases in the liver to produce the active parent dicarboxylic acid, ENALAPRILAT?
Enalapril
Fact for ENALAPRIL
○ 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
What is a lysine analog of Enalaprilat?
Lisinopril
LISINOPRIL facts
○ 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.
BENAZEPRIL facts
○ 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)
FOSINOPRIL facts
○ 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.
TRANDOLAPRIL facts
○ 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.
QUINAPRIL facts
○ 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)
RAMIPRIL facts
○ 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)
What is a prodrug whose antihypertensive activity is almost entirely due to its deesterified metabolite, MOEXIPRIL???
MOEXIPRIL
MOEXIPRIL facts
○ 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.
PERINDOPRIL
○ 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)
Therapeutic Uses
of ACE inhibitors:
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
Adverse Effects of ACE inhibitors:
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.
Angiotensin II - Receptor Antagonists or
Blockers (ARB)
MOA
● 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.
Pharmacologic Effects of ARBs
● 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
Pharmacokinetics ARBs
● Oral bioavailability is generally low (<50%); except for Irbesartan (70%)
● Protein binding is high (>90%)
ARBs and their differences:
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
Therapeutic Uses
of ARBs
- Treatment of hypertension — the only approved therapeutic indication
- Reserve for treatment of heart failure in patients who cannot tolerate or have an unsatisfactory response to ACE inhibitors.
- Treatment of partial hypertension in patients with cirrhosis and portal hypertension without compromising renal function — Losartan
Adverse Effects of ARBs:
- Angioneurotic edema — incidence is lesser compared to ACE inhibitors
-
Fetopathic potential
○ Should be discontinued before the 2nd trimester of pregnancy. - Hyperkalemia in patients with renal disease or in patients taking K+ supplement or K - sparing drugs.
