Month: September 2015

The Management of Hypertension (Interventions)

September 17, 2015 Uncategorized No comments , , , , , ,

Overall Goals

The overall goal of treating hypertension is to reduce hypertension-associated morbidity and mortality. This morbidity and mortality is related to hypertension-associated target-organ damage (e.g., ASCVD, retinopathies, cerebrovascular events, heart disease, kidney disease, and PAD etc.). Reducing CV risk is the primary purpose of hypertension therapy and the specific choice of drug therapy should be determined by evidence demonstrating such CV risk reduction.

Above overall target should be interpreted more deeper. According to JNC 7 guideline, hypertension patients can be divided into two groups, one with compelling indications, most of which are CV diseases but not necessarily due to hypertension (e.g., non-hypertension associated CKD, DM), one without compelling indications. For patients without compelling indications (no existed CV diseases or CV diseases non-detectable), the therapy is to reduce the risk of hypertension-associated CV (primary prevention). For patients with compelling indications which are non-hypertension-associated, for example, hypertension plus diabetes or non-hypertension-associated CKD, the therapy is to reduce the risk of hypertension-associated CV (primary prevention) and to reduce the morbidity and mortality of the compelling condition. For patients with compelling indications which are hypertension-associated,  the therapy is to slow the progression of hypertension and existed CV diseases or secondary prevention (e.g., Post-MI).


BP Goals

Because elevated BP level is related to CV risk/risk of hypertension-associated target-organ damage, which whereas involved with morbidity and mortality of hypertension, to achieve a desire target BP value is simply a surrogate goal of therapy. For primary prevention, reducing BP to goal does not guarantee prevention of hypertension-associated target-organ damage, but is associated with a lower risk of hypertension-associated target-organ damage.

The latest JNC 8 hypertension guideline category hypertension patients into four groups, including

  • Patients without diabetes or CKD >=60 years of age
  • Patients without diabetes or CKD <60 years of age
  • Patients with diabetes but no CKD
  • Patients with CKD

Each category has its target BP goal, as shown in the Figure 1 below.

In the general population aged 60 years or older, initiate pharmacologic treatment to lower BP at systolic blood pressure (SBP) of 150 mm Hg or higher or diastolic blood pressure (DBP) of 90 mm Hg or higher and treat to a goal SBP lower than 150 mm Hg and goal DBP lower than 90 mm Hg (Strong recommendation – Grade A). In the general population aged 60 years or older, if pharmacologic treatment for high BP results in lower achieved SBP (for example, <140 mm Hg) and treatments is not associated with adverse effects on health or quality of life, treatment does not need to be adjusted (Expert opinion – Grade E).

In the general population younger than 60 years, initiate pharmacologic treatment to lower BP of 90 mm Hg or higher and treat to to a goal DBP of lower than 90 mm Hg (For ages 30 through 59 years, strong recommendation – Grade A; for ages 18 through 29 years, expert opinion – Grade E).

In the general population younger than 60 years, initiate pharmacologic treatment to lower BP at SBP of 140 mm Hg or higher and treat to a goal SBP of lower than 140 mm Hg (Expert opinion – Grade E).

For more information about the JNC 8’s BP goals please visit the American Medical Association at http://jama.jamanetwork.com/article.aspx?articleid=1791497.


General Approach to Treatment

Most patients should be placed on both lifestyle modifications and drug therapy concurrently after a diagnosis of hypertension is made. Life-style modification alone is appropriate for most patients with prehypertension. However, lifestyle modifications alone may not be adequate for patients with either additional CV risk factors (in so, not adequate to reduced the CV risk) or hypertension-associated target-organ damage (secondary prevention/slow the progression of existed hypertension-associated target-organ damage).

Besides hypertension, other major and additional CV risk factors should be avoided if possible (e.g., smoking). Major and additional risk factors can be found at http://www.tomhsiung.com/wordpress/2014/07/the-management-of-dyslipidemia/

Choice of Initial Drug Therapy

The choice of initial drug therapy depends on the degree of BP elevation and presence of compelling indications (HFrEF, Post-MI, CAD, DM, CKD, and Recurrent Stroke Prevention). Most patients with stage 1 hypertension should be initially treat with a first-line antihypertensive drug or the combination of two agents. Combination drug therapy is recommended for patients with more severe BP elevation (stage 2 hypertension), using preferably two first-line antihypertensive drug.

It is important to remember that the general goal to treat hypertension patients without compelling is to reduce the risk or slow the progress of hypertension-associated target organ damage.


Treatment

Nonpharmacologic Therapy

All patients with prehypertension and hypertension should be prescribed lifestyle modifications. Recommended modifications that have been shown to lower BP are list in Table 3-4. They can provide small to moderate reductions in SBP. Aside from lowering BP in patients with known hypertension, lifestyle modification can decrease the progression to hypertension in patients with prehypertension BP values.

Table 3-4 Lifestyle Modifications to Prevent and Manage Hypertension

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Pharmacotherapy – No Compelling Indications

First line antihypertensive agents include thiazide, ACEI, ARB, and CCB. They should be used to treat the majority of patients with hypertension because evidence from outcome data have demonstrated CV risk reduction benefits with these classes. As we discussed earlier, the overall goal of management of hypertension is to reduce hypertension-associated morbidity and mortality. This morbidity and mortality is related to hypertension-associated target-organ damage (e.g., CV events, retinopathies, cerebrovascular events, heart failure, kidney disease, and PAD etc.) and therefore reducing CV risk is the primary purpose of hypertension therapy and the specific choice of drug therapy should be determined by evidence demonstrating such CV risk reduction. So the efficacy (clinical outcome) of antihypertensive agents could be measured by comparing the reduction of the CV risk of each drug.

Evidence from ALLHAT trial showed that therapeutic arm of chlorthalidone, compared with lisinopril or amlodipine, respectively, are of no significant differences in the primary end point (fatal CHD and nonfatal MI). However, chlorthalidone had statistically fewer secondary end points than amlodipine (heart failure) and lisinopril (combined CV disease, heart failure, and stroke).

Figure 1 Patient Criteria for ALLHAT Trial 

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PS: Detail information for ALLHAT trail could be found at https://clinicaltrials.gov/ct2/show/study/NCT00000542?term=allhat&rank=3. Note that 36 percent of all patients enrolled were diabetics.

Clinical trial data cumulatively demonstrate that ACEI-, CCB-, or ARB-based antihypertensive therapy reduces CV events. These agents may be used for patients without compelling indications as a first-line therapy.

Clinical trial data cumulatively suggest that beta-blockers may not reduce CV events to the extent that ACEIs, ARBs, or thiazide diuretics do. Available data from meta-analyses demonstrated fewer reductions in CV events with beta-blocker-based antihypertensive therapy compared mostly with ACEI-, and CCB-based therapy. However, it is important for clinicians to remember that beta-blocker-based antihypertensive therapy does not increase risk of CV events; beta-blocker-based therapy reduces risk of CV event compared with no antihypertensive therapy. Using a beta-blocker as a primary antihypertensive agent is optimal when an ACEI, ARB, or thiazide diuretic cannot be used as the primary agent. Besides, beta-blocker still have an important add-on role after first-line agents to reduce BP in patients with hypertension but without compelling indications.

Pharmacotherapy – With Compelling Indications

The JNC 7 report identifies six compelling indications. Compelling indications represent specific comorbid conditions where evidence from clinical trials supports using specific antihypertensive classes to treat both the compelling indiction and hypertension. Drug therapy recommendations typically consist of combination drug therapies. Data from these clinical trials have demonstrated reduction in CV morbidity and/or mortality that justify use for patients with hypertension and with such a compelling indication.

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  • HFrEF (ACEI or ARB + Diuretic, then add Beta-Blocker. Aldosterone receptor antagonist is add-on therapy).

Five drug classes are list as compelling indications for HFrEF. An evidence-based pharmacotherapy regimen for HFrEF, sometimes called standard pharmacotherapy, consists of three to four drugs: an ACEI or ARB plus diuretic therapy, followed by the addition of an appropriate beta-blocker, and possibly an aldosterone receptor antagonist. Evidence from clinical trials shows that ACEIs significantly modify disease progression by reducing morbidity and mortality. Although HFrEF was the primary disease in these studies, ACEI therapy will also control BP in patient with HFrEF and hypertension. ARBs are acceptable as an alternative therapy for patients who cannot tolerate ACEIs based on data from the CHARM studies (https://clinicaltrials.gov/ct2/show/NCT00634309?term=assessment+of+reduction+in+mortality+and+morbidity&rank=1). An ACEI or ARB should be started with low doses for patients with HFrEF, especially those in acute exacerbation. Heart failure induces a compensatory high-rennin condition, and starting ACEI inhibitors or ARBs under these conditions can cause a pronounced first-dose effect and possible orthostatic hypotension.

Diuretics are also a part standard pharmacotherapy primarily to control symptoms. They provide symptomatic relief of edema by inducing diuresis. Loop diuretics are often needed, especially for patients with more advanced heart failure. However, some patients with well-controlled heart failure and without significant CKD may be managed with a thiazide diuretic.

Beta-blocker therapy is appropriate to further modify disease in HFrEF and is a component of standard therapy for these patients. For patients on an initial regimen of diuretics and ACEIs, beta-blockers have been shown to reduce CV morbidity and mortality. It is of paramount importance that beta-blockers be doses appropriately due to the risk of including an acute exacerbation of heart failure. They must be started in very low doses, does much lower than that used to treat hypertension, and titrated slowly to high doses based on tolerability. Bisoprolol, carvedilol, and sustained-release metoprolol succinate are the only beta-blockers proven to be beneficial in HFrEF.

After implementation of a standard three-drug regimen (diuretic, ACEI or ARB, and beta-blocker), other agents may be added to further reduce CV morbidity and mortality, and reduce BP if needed. The addition of an aldosterone antagonist can reduce CV morbidity and mortality in HFrEF. Spironolactone has been studied in severe HFrEF and has shown benefit in addition to diuretic and ACEI therapy.

  • Post-MI (Beta-Blocker, then add ACEI or ARB)

Beta-blockers (those without intrinsic sympathomimetic activity [ISA]) and ACEI inhibitor or ARB therapy are recommended in the AHA/ACC Foundation and JNC 7 guidelines. Beta-blockers decrease cardiac adrenergic stimulation and have been shown in clinical trials to reduce the risk of a subsequent MI or sudden cardiac death. ACEIs have been shown to improve cardiac remodeling and cardiac function and to reduce CV events post-MI. These two drug classes, with beta-blockers first, are considered the first drugs of choice for patients who have experienced an MI. One study, the VALIANT trial, demonstrated that ARB therapy is similar to ACEI therapy for patients post-MI heart failure and/or left ventricular systolic dysfunction.

  • Coronary Artery Disease (Beta-Blocker, then add ACEI or ARB. CCB or Thiazide Diuretic are add-on agents)

Beta-blocker therapy has been considered a standard of care for treating patients with coronary artery disease and hypertension. Beta-blockers are first-line therapy in chronic stable angina and have the ability to reduce BP and improve ischemic symptoms by decreasing myocardial oxygen consumption and demand. Beta-blockers therapy seems to be most effective in reducing the risk of CV events in patients with recent MI and/or ischemic symptoms. Long-acting CCBs may considered alternatives to beta-blockers (diltiazem and verapamil) or as add-on therapy (dihydropyridine CCBs) in chronic stable angina for patients with ischemic symptoms.

For acute coronary syndromes, first-line therapy should consist of a beta-blocker and ACEI. An ARB is a reasonable alternative to an ACEI.

  • Diabetes Mellitus (ACEI or ARB, CCB, Thiazide Diuretic, or Beta-Blocker might be add-on agents)

All patients with diabetes and hypertension should ideally be treated with an ACEI or an ARB. The reason is that, pharmacologically, both of these agents should provide nephroprotection due to vasodilation in the efferent arteriole of the kidney. CCBs are the most appropriate add-on agents for BP control for patients with diabetes.

  • CKD (ACEI or ARB)

Patients with hypertension may develop damage to either the renal tissue or the renal arteries. The rate of kidney function deterioration is accelerated when both hypertension and diabetes are present. Once patients have an estimated GFR <60 mL/min/1.73 m2 or albuminuria, they have significant CKD and risk of CV disease and progression to severe CKD increases. BP Control can slow the decline in kidney function.

In addition to lowering BP, ACEIs and ARBs reduce intraglomerular pressure, which can theoretically provide additional benefits by further reducing the decline in kidney function. ACEIs and ARBs have been shown to reduce progression of CKD in diabetes and in those without diabetes. However, it is difficult to differentiate whether the kidney protection benefits are from RAAS blockade versus BP lowering.

  • Recurrent Stroke Prevention (Thiazide with/without ACEI)

Ischemic stroke (not hemorrhagic stroke) and transient ischemic attack are considered a form of hypertension-associated target-organ damage. Attaining goal BP values in patients who have experienced an ischemic stroke is considered a primary modality to reduce risk of a second stroke. A thiazide diuretic, either in combination with an ACEI or as monotherapy, is considered an evidence-based antihypertensive regimen for patients with a history of stroke or transient ischemic attack. Antihypertensive drug therapy should only be implemented after patients have stabilized following an acute cerebrovascular event.

Combination Therapy

Initial therapy with a combination of two drugs is highly recommended for patients with stage 2 hypertension and is an option of retreating patients with stage 1 hypertension. Also initial two-drug combination therapy may be appropriate for patients with multiple compelling indications for different antihypertensive agents. Clinicians should anticipate the need for combination drug to control BP in most patients. Besides, using low-dose combinations provides greater reductions in BP compared with high doses of single agents and appropriately increasing the number of antihypertensive medications to attain goal BP values does not increase the risk of adverse effects.

The Management of Hypertension (Clinical Evaluation)

September 12, 2015 Cardiology, Diabetes, Infectious Diseases, Pharmacotherapy, Therapeutics No comments , , , , , , , ,

Frequently, the only sign of essential hypertension is elevated BP. The rest of the physical examination may be completely normal. However, a complete medical evaluation including a comprehensive medical history, physical examination, and laboratory and/or diagnostic test is recommended after diagnosis to identify secondary causes, identify other CV risk factors or comorbid conditions that may define prognosis and/or guide therapy, and assess for the presence of absence of hypertension-associated target-organ damage.

For the patients who have been diagnosed with hypertension, we should ask a few questions that are necessary to make a clinical evaluation for these patients. Here is an example of a patient with hypertension.

D.C. is a 44-year-old black man who presents to his primary care provider concerned about high BP. At an employee health screening last month he was told he has stage 1 hypertension. His medical history is significant for allergic rhinitis. His BP was 144/84 and 146/86 mm Hg last year during an employee health screening at work. D.C.’s father had hypertension and died of an MI at age 54. His mother had diabetes and hypertension and died of a stroke at age 68. D.C. smokes on pack per day of cigarettes and thinks his BP is high because of job-related stress. He does not engage in any regular exercise and does not restrict his diet in any way, although he knows he should lose weight.

Physical examination show he is 175 cm tall, weighs 108 kg (BMI, 35.2 kg/m2), BP is 148/88 mm Hg (left arm) and 146/86 mm Hg (right arm) while sitting, heart rate is 80 beats/minute. Six months ago, his BP values were 152/88 mm Hg and 150/84 mm Hg when he was seen by his primary-care provider for allergic rhinitis. Funduscopic examination reveals mild arterial narrowing and arteriovenous nicking, with no exudates or hemorrhages. The other physical examination findings are essentially normal.

D.C.’s fasting laboratory serum values are as follows:

Blood urea nitrogen, 24 mg/dL

Creatinine, 1.0 mg/dL

Glucose, 105 mg/dL (Fasting?)

Potassium, 4.4 mEq/L

Uric acid, 6.5 mg/dL

Total cholesterol, 196 mg/dL

Low-density lipoprotein cholesterol, 141 mg/dL

High-density lipoprotein cholesterol, 32 mg/dL

Triglycerides, 170 mg/dL

An electrocardiogram is normal except for left ventricular hypertrophy.

PS: Normal values are marked in green and abnormal values are marked in orange.


Clinical Presentation

Question 1 What is the clinical presentation D.C.?

All the information above could be the part of D.C.’s clinical presentation. Besides, we could classify the stage of D.C.’s hypertension as shown below.

D.C. has uncontrolled stage 1 hypertension. He has had elevated BP values, measured in clinical environments, and meets the diagnostic criteria for hypertension because two or more of his BP measurements are elevated on separate days. SBP values are consistently stage 1, whereas DBP values are all in the prehypertension range. The higher of the two classifications is used to classify hypertension.

Question 2 Why does D.C. have hypertension?

D.C. has essential hypertension; therefore, the exact cause is not known. He has several characteristics (e.g., family history of hypertension, obesity) that may have increased his chance of developing hypertension. Race and sex also influence the prevalence of hypertension Across all age groups, black have a higher prevalence of hypertension than do whites and Hispanics. Similar to other form of CV disease, hypertension is more server, more like to include hypertension-associated complications, and occurs at an earlier age in black patients.


Patient Evaluation and Risk Assessment

The presence of absence of hypertension-associated complications as well as other major CV risk factors (Table 14-5) must be assessed in D.C. Also, secondary cause of hypertension (Table 14-3), if suggested by history and clinical examination findings, should be identified and managed accordingly. The presence of concomitant medical conditions (e.g., diabetes) should be assessed, and lifestyle habits should be evaluated so that they can be used to guide therapy.

  • Hypertension-associated complications
  • Secondary causes of hypertension
  • Concomitant medical conditions

Question 3 Dose D.C. has secondary cause of hypertension?

The most common secondary causes of hypertension are list in Table 3-1. Patients with secondary hypertension might have signs or symptoms suggestive of the underlying disorders.

Table 3-1 Secondary Causes of Hypertension.

  • Patients with pheochromocytoma may have a history of paroxysmal headaches, sweating, tachycardia, and palpitations. Over half of these patients suffer from episodes of orthostatic hypotension.
  • In primary hyperaldosteronism symptoms related to hypokalemia usually include muscle cramps and muscle weakness.
  • Patients with Cushing’s syndrome may complain of weight gain, polyuria, edema, menstrual irregularities, recurrent acne, or muscle weakness and have several classic physical features (e.g., moon face, buffalo hump, hirsutism).
  • Patient with coarctation of the aorta may have higher BP in the arms than in legs and diminished or even absent femoral pulses.
  • Patient with renal artery stenosis may have an abdominal systolic-diastolic bruit.

Also, routine laboratory tests may also help identify secondary hypertension. For example, Baseline hypokalemia may suggest mineralocorticoid-induced hypertension. Protein, red blood cells, and casts in the urine may indicate renovascular disease. Some laboratory tests are used specifically to diagnose secondary hypertension. These include plasma norepinephrine and urinary metanephrine for pheochromocytoma, plasma and urinary aldosterone concentrations for primary hyperaldosteronism, and plasma rennin activity, captopril stimulation test, renal vein renin, and renal artery angiography for renoascular disease.

Certain drugs and other products can result in drug-induced hypertension. For some patients, the addition of these agents can be the cause of elevated BP or can exacerbate underlying hypertension. Identify a temporal relationship between starting the suspected agent and developing elevated BP is most suggestive of drug-induced BP elevation.

Question 4 Which hypertension-associated complications are present in D.C.?

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A complete physical examination to evaluate hypertension-associated complications includes examination of the optic funds; auscultation for carotid, abdominal, and femoral bruits; palpation of the thyroid gland; heart and lung examination; abdominal examination for enlarged kidney, masses, and abnormal aortic pulsation; lower extremity palpation for edema and pulses; and neurologic assessment. Routine laboratory assessment after diagnosis should include the following: EKG; urinalysis; fasting glucose; hematocrit; serum potassium, creatinine, and calcium; and fasting lipid panel. Optional testing may include measurement of urinary albumin excretion or albumin-to-creatinine ratio, or additional tests specific for secondary causes if suspected.

Question 5 What other forms of hypertension-associated complications is D.C. at risk for?

Hypertension adversely affects many organ systems, including the heart, brain, kidneys, peripheral circulation, and eyes (Table 14-5). Damage to these systems resulting from hypertension is termed hypertension-associated complications, target-organ damage, or CV disease. There are often misconceptions about the term CV disease and CAD. CV disease encompasses the broad scope of all forms of hypertension-associated complications. CAD is simply a subset of CV disease and refers specifically to disease related to the coronary vasculature, including ischemic heart disease and MI.

Hypertension can affect the heart either indirectly, by promoting atherosclerotic changes, or directly, via pressure-related effects. Hypertension can promote CV disease and increase the risk for ischemic events, such as angina and MI. Antihypertensive therapy has been shown to reduce the risk of these coronary events. Hypertension also promotes the development of LVH, which is a myocardial (cellular) change, not an arterial change. These two conditions often coexist, however. It is commonly believed that LVH is a compensatory mechanism of the heart in response to the increased resistance caused by elevated BP (more accurately, the afterload). Recall the definition of afterload, that is, wall tension=(pressure * radius)/(wall thickness). LVH is a strong and independent risk factor for CAD, left ventricular dysfunction, and arrhythmia. LVH does not indicate the presence of left ventricular dysfunction, but is a risk for progression to left ventricular dysfunction, which is considered a hypertension-associated complication. This may be caused by ischemia, excessive LVH, or pressure overload. Ultimately, left ventricular dysfunction results in a decrease ability to contract (systolic dysfunction).

Hypertension is one of the most frequent causes of cerebrovascular disease. Cerebrovascular signs can manifest as transient ischemic attacks, ischemic strokes, multiple cerebral infarcts, and hemorrhages. Residual functional deficits caused by stroke are among the most devastating forms of hypertension-associated complications. Clinical trials have demonstrated that antihypertensive therapy can significantly reduce the risk of both initial and recurrent stroke. A sudden, prolonged increase in BP also can cause hypertensive encephalopathy, which is classified as a hypertensive emergency.

The GFR is used to estimate kidney function, which declines with aging. This rate of decline is greatly accelerated by hypertension. Hypertension is associated with nephrosclerosis, which is caused by increased intraglomerular pressure. It is unknown whether a primary kidney lesion with ischemia causes systemic hypertension or whether systemic hypertension directly causes glomerular capillary damage by increasing intraglomerular pressure. Regardless, CKD, whether mild or severe, can progress to kidney failure (stage 5 CKD) and the need for dialysis. Studies have demonstrated that controlling hypertension is the most important strategy to slow the rate of kidney function decline, but it may not be entirely effective in slowing the progression of renal impairment in all patients.

In hypertension, stage 3 CKD or worse is considered a hypertension-associated complication (GFR values of <60 mL/min/1.73 m2). An estimated GFR of less than 60 mL/min/1.73 m2 corresponds approximately to a serum concentration of greater than 1.5 mg/dL in an average man and greater than 1.3 mg/dL in an average woman. This level of kidney compromise lowers an individual’s BP goal to less than 130/80 mm Hg according to multiple guidelines. The presence of persistent albuminuria (>300 mg albumin in a 24-hour urine collection or 200 mg albumin/g creatinine on a spot urine measurement) also indicates significant CKD, for which achieving the more aggressive BP goal is a strategy to minimize the rate of progression to kidney failure.

Peripheral arterial disease, a non coronary form of atherosclerotic vascular disease, is considered a hypertension-associated complication. It is equivalent in CV risk to CHD. Risk factor reduction, BP control, and anti platelet agent(s) are needed to decrease progression. Complications of peripheral arterial disease can include infection and necrosis, which in some cases require revascularization procedures or extremity amputation.

Hypertension causes retinopathies that can progress to blindness. Retinopathy is evaluated according to the Keith, Wagener, and Barker funduscopic classification system. Grade 1 is characterized by narrowing of the arterial diameter, indicating vasoconstriction. Arteriovenous nicking is the hallmark of grade 2, indicating atherosclerosis. Longstanding, untreated hypertension can cause cotton wool exudates and flame hemorrhages (grade 3). In severe cases, papilledema occurs, and this is classified as grade 4.

Question 6 Which major CV risk factors are present in D.C.?

As shown in Table 14-5, major CV risk factors include advanced age (>55 years for men, >65 years for women), cigarette smoking, diabetes mellitus, dyslipidemia, family history of premature atherosclerotic vascular disease (men <55 years or women <65 years) in primary relatives, hypertension, kidney disease (microablubuminuria or estimated GFR <60 mL/min/1.73 m2), obesity (BMI >=30 kg/m2), and physical inactivity.

PS: Estimated GFR calculated from online calculator for D.C. is 105 mL/min/1.73 m(online calculator: http://www.davita.com/gfr-calculator/).

So according to D.C.’s clinical presentation, he has major CV risk factors that are marked in orange, that is, 5 factors in total, including the essential hypertension.

Question 7 What is D.C.’s BP goal and how can Framingham risk scoring influence BP goal determination?

D.C. is a primary prevention patient because he does not yet have any hypertension-associated compilations (or compelling indications). He has multiple CV risk factors, so controlling his BP is of paramount importance to reduce the risk of developing hypertension-associated complications. The JNC-8 guidelines recommend the initial BP goal for hypertension patients with age of <60 years should be 140/90 mm Hg, which has grade A evidence (strong recommendation) for patients from 30 through 59 years of age, and grade E (expert opinion) for those from 18 through 29 years of age. So D.C.’s initial BP goal should be below 140/90 mm Hg.

The framingham risk scoring system is available as an online calculator at NIH site of http://cvdrisk.nhlbi.nih.gov/calculator.asp. According to D.C.’s clinical presentation, he will has a CV risk of  14% in a next 10-year period of expectation before we intervention, which means in a population cohort such as D.C., 14 in 100 individuals will develop CV diseases after a period of 10-year, if we don’t treat these CV risk factors (if these risk factors worsen, the incidence of developing CV diseases would be higher). If we treat D.C.’s current hypertension target the BP goal, with other interventions that target D.C.’s rest risk factors like habit of smoking, etc., the incidence of developing CV diseases would be attenuated (In D.C.’s example, the incidence would decrease to 5%, that is 5 in 100 of individuals will develop CV diseases in a period of 10-year). Compare the results without/with interventions to D.C.

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The intervention above does not include the management of dyslipidemia. According to the latest AHA guideline, four types of patients need the intervention for dyslipidemia, including: 1.secondary prevention in individuals with clinical ASCVD; 2. primary prevention in individuals with primary elevations of LDL-C >=190 mg/dL; 3.primary prevention in individuals with diabetes 40 to 75 years of age who have LDL-C 70 to 189 mg/dL; and 4.primary prevention in individual without diabetes and with estimated 10-year ASCVD risk>=7.5%, 40 to 75 years of age who have LDL-C 70 to 189 mg/dL. (References: http://www.tomhsiung.com/wordpress/2014/07/the-management-of-dyslipidemia/). So we need to calculate D.C.’s ASCVD risk from another tool developed by ACC/AHA (American College of Cardiology/American Heart Association), which is available as iOs apps. So the result of ASCVD risk of D.C. is 9.7% (>=7.5%) without any intervention, whereas ASCVD risk is 8.6% (still >=7.5%) with interventions of antihypertensive therapy and smoke cessation. Therefore, the dyslipidemia should be treated for D.C.

PS: ASCVD includes coronary heart disease (CHD), stroke, and peripheral arterial disease, all of presumed atherosclerotic origin.

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The Management of Hypertension (Pathophysiologic Basises)

September 10, 2015 Cardiology, Pharmacology, Physiology and Pathophysiology No comments , , , , , , , , , , ,

Hypertension is a common diseases and is defined as persistently elevated arterial blood pressure of >= 140/90 mm Hg. Most of patients belong to essential hypertension and a small percentage belong to secondary hypertension for which the most common causes include renal dysfunction resulting from severe chronic kidney disease (CKD) or renovascular disease. Besides, certain drugs or other products (Table 3-1), either directly or indirectly, can cause hypertension or exacerbate hypertension by increase BP.

Table 3-1 Secondary Causes for Hypertesnion

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Classification of Hypertension

  • Normal: Systolic lower than 120 mm Hg, diastolic lower than 80 mm Hg
  • Prehypertension: Systolic 120-139 mm Hg, diastolic 80-89 mm Hg
  • Stage 1: Systolic 140-159 mm Hg, diastolic 90-99 mm Hg
  • Stage 2: Systolic 160 mm Hg or greater, diastolic 100 mm Hg or greater

Hypertension Crisis: These are clinical situations where BP values are very elevated, typically >180/120 mm Hg. They are categorized as either hypertensive emergency or hypertensive urgency. The former are extreme elevations in BP that are accompanied by acute or processing target-organ damage. The latter are high elevations in BP without acute or progressing target-organ injury. Prehypertension is not considered a disease category but identifies patients whose BP is likely to increase into the classification of hypertension in the future.

Cardiovascular Risk and Blood Pressure

Hypertension must be treated and the reason why is that hypertension is a major cardiovascular risk factor and there indeed is a causal relationship between hypertension and cardiovascular diseases. Also, epidemiologic data demonstrate a strong correlation between BP and CV morbidity and mortality. (Starting at a BP of 115/75 mm Hg, risk of CV disease doubles with every 20/10 mm Hg increase.) Even patients with prehypertension have an increased risk of CV disease. Because hypertension and CV morbidity/mortality has a casual relationship, treating patients with hypertension with antihypertensive drug therapy provides significant clinical benefits.


Pathophysiology

To further discuss the pathophysiology, we first need to know the mathematic formula to estimate arterial BP. According to the physic law, steady flow (Q) through a closed hydraulic circuit is directly related to the pressure gradient across the circuit (Pin – Pout), and inversely related to the resistance to flow (R) through the circuit. So Q=(Pin – Pout)/R. In the cardiovascular system, Q is cardiac output (CO), Pin is mean arterial pressure (MAP) and Pout is right atrial pressure (RAP), whereas resistance to flow (R) is total peripheral resistance (TPR). So CO=(MAP – RAP)/TPR. Because in normal conditions RAP approaches zero mm Hg, so CO=MAP/TPR and after we make a rearrange we finally get the formula of MAP=CO * TPR. Note that in some pathophysiology status RAP increases significantly and cannot be removed from the formula above.

After the discuss above, the two determinants for MAP is the cardiac output (CO) and the total peripheral resistance (TPR). If we distinguish MAP to systolic BP (SBP) and diastolic BP (DPB), CO is the major determinant of SBP, whereas TPR largely determines DBP. So factors that elevate CO or TPR can elevate BP. We category these factors into 1.humoral; 2.neuronal; 3.peripheral autoregulation; and 4.disturbances in sodium, calcium, and natriuretic hormone.

Humoral Mechanisms

RAAS

RAAS stands for the rennin-angiotensin-aldosterone system, which is a complex endogenous system that play a range of functions including the regulation of arterial pressure. The RAAS regulars sodium, potassium, blood volume, and most important the vascular tone. Because the total periphery resistance (TPR) is primarily generated by arterioles, so elevated TPR could be a result of activation of RAAS – the angiotensin II (angII). For the detail discussion of TPR please refer to the threads of http://www.tomhsiung.com/wordpress/2015/06/flow-resistance-of-vessels-in-series-and-vessels-in-parallel/ and http://www.tomhsiung.com/wordpress/2015/07/vascular-resistances-and-compliance-map-and-pulse-pressure/, respectively, by Tom Hsiung. First, angII increase the vascular tone, including arterioles. Second, angII induced increased aldosterone synthesis and secretion sodium and water retention, which increase the blood volume. Increased blood volume and TPR eventually result in elevation of BP.

Vasopressin

Vasopressin is a polypeptide hormone, also known as antidiuretic hormone/ADH, which plays an important role in extracellular fluid homeostasis (blood volume/plasma volume). Vasopressin acts on collecting ducts in the kidneys to decrease renal excretion of water. This is the most important and wide-known function of vasopressin. However, vasopressin is also a potent arteriolar vasoconstrictor.

Natriuretic Hormone

Natriuretic hormones inhibits sodium and potassium-ATPase and thus interferes with sodium transport across cell membranes. Natriuretic hormone theoretically could increase urinary exertion of sodium and water. However, this hormone might block the active transport of sodium out of arteriolar smooth muscle cells. The increased intracellular sodium concentration concentration ultimately would increase vascular tone and BP.

Insulin Resistance and Hyperinsulinemia

Hypothetically, increased insulin concentrations may lead to hypertension because of increased renal sodium retention and enhanced sympathetic nervous system activity. Moreover, insulin has growth hormone-like actions that can induce hypertrophy of vascular smooth muscle cells. Insulin also may elevated BP by increasing intracellular calcium, which lead to increased vascular resistance. The exact mechanism by which insulin resistance and hyperinsulinemia occur in hypertension is unknown. However, this association is strong because many of the criteria used to define this population (i.e., elevated BP, abdominal obesity, high, triglycerides, low high-density lipoprotein cholesterol, and elevated fasting glucose) are often present in patients with hypertension.

Circulating Catecholamines

It is easy to understand the causal relationship between elevated levels of circulating catecholamines and the hypertension, from the perspective of MAP = CO * TPR.

Neuronal Regulation

Synaptic receptors, baroreceptor reflex system, and CNS are involved in the regulation of vascular resistances, cardiac outputs.

Central and autonomic nervous system are intricately involved in the regulation of arterial BP. Many receptors that either enhance or inhibit norepinephrine release are located on the presynaptic surface of sympathetic terminals. The alpha and beta presynaptic receptors play a role in negative and positive feedback to the norepinephrine-containing vesicles, respectively. Stimulation presynaptic alpha-receptors (α2) exerted a negative inhibition on norepinephrine release. Stimulation of presynaptic beta-receptors facilitates norepinephrine release.

Sympathetic neuronal fibers located on the surface of effector cells innervate the alpha- and beta-receptors. Stimulation of postsynaptic alpha-receptors (α1) on arterioles and venues results in vasoconstriction. There are two types of postsynaptic beta-receptors, β1 and β2. Both are present in all tissues innervated by the sympathetic nervous system. However, in some tissues β1-receptors predominate (e.g., heart), and in other tissues β2-receptors predominate (e.g., bronchioles). Stimulation of β1-receptors in the heart results in an increase in heart rate, and the force of contraction (so cardiac output is increased), whereas stimulation of β2-receptors in the arterioles and venues causes vasodilation.

So after the discussion of the two paragraph above, we know that the disturbance of the function of presynaptic and/or postsynaptic receptors would result the imbalance of autonomic nervous system.

Same with the autonomic nervous system but from a different aspect (above is output of autonomic nervous system and now it’s the input of nervous system),  the baroreceptor reflex system is the major negative feedback mechanism the controls sympathetic activity. Baroreceptors are nerve endings lying in the walls of large arteries, especially in the carotid arteries and aortic arch. Changes in arterial BP rapid activate baroreceptors that then transmit impulses to the brain stem through the ninth cranial nerve and vagus nerve. In this reflex system, a decrease in arterial BP stimulates baroreceptors, causing reflex vasoconstriction and increased heart rate and force of cardiac contraction. Also the periphery vascular tone increase too (TPR).

Stimulation of certain areas within the central nervous system can either increase or decrease BP. I think this mechanism must be rather complex, which involves with neurology. If we have time in future, I will take a look at the neurology.

OK. The purpose of the neuronal mechanisms is to regulate BP and maintain homeostasis. Pathologic disturbances in neuronal systems could chronically elevate BP. These systems are physiologically interrelated. A defect in one component may alter normal function in another. Therefore, cumulative abnormalities may explain the development of essential hypertension.

Peripheral/Local Mechanisms (including autoregulatory, etc.) 

Abnormalities in renal or tissue autoregulatory systems, which is just one of several local vascular regulatory mechanisms of human, could cause hypertension. Recall the formula that MAP = CO * TPR. Similarly, the disorders of local vascular regulatory .For detail information of local vascular regulatory mechanisms please refer to the thread of http://www.tomhsiung.com/wordpress/2015/07/arteriolar-tone-and-its-regulation-local-mechanisms/ by Tom Hsiung.

Electrolytes

Epidemiologic and clinical data have associated excess sodium intake with hypertension. Population-based studies indicate that high-sodium diets are associated with a high prevalence of stroke and hypertension. Conversely, low-sodium diets are associated with a lower prevalence of hypertension. For the perspective of pathophysiology, more sodium, more water. We will discuss this phenomenon in threads that discuss the kidney.

Altered calcium homeostasis also may play an important role in the pathogenesis of hypertension. A lack of dietary calcium hypothetically can disturb the balance between intracellular and extracellular calcium, resulting in an increased intracellular calcium concentration. This imbalance can alter vascular smooth muscle function by increasing PVR (peripheral vascular resistance). Some studies have shown that dietary calcium supplementation results in a modest BP reduction for patients with hypertension.

The role of potassium fluctuations is also inadequately understood. Potassium depletion may increase PVR, but the clinical significance of small serum potassium concentration changes is unclear. Furthermore, data demonstrating reduced CV risk with dietary potassium supplementation are very limited.

Control of Venous Tone

September 9, 2015 Cardiology, Physiology and Pathophysiology No comments ,

Before considering the details of the control of venous tone, recall that venues and veins play a much different role in the cardiovascular system than do arterioles. Arterioles are the inflow valves that control the rate of nutritive blood flow through organs and individual regions within them.

Appropriately, arterioles are usually strongly influenced by the current local metabolic needs of the region in which they reside, whereas veins are not. Veins, do, however, collectively regulate the distribution of available blood volume between the peripheral and central venous compartments. Recall that central blood volume (and therefore pressure/cardiac filling pressure) has a marked influence on stroke volume and cardiac output. Consequently, when one considers what peripheral veins are doing, one should be thinking primarily about what the effects will be on central venous pressure and cardiac output.

PS: With other factors equal, stroke volume increases as cardiac filling increases.

Veins contain the vascular smooth muscle that is influenced by many things that influence the vascular smooth muscle of arterioles. Constriction of the vein is largely mediated through activity of the sympathetic nerves that innervate them. As in arterioles, these sympathetic nerves release norepinephrine, which interacts with α1-receptors and produces an increase in venous tone and a decrease in vessel diameter. There are, however, several functionally important differences between veins and arterioles. Compared with arterioles, veins normally have little basal tone. Thus, veins are normally in a dilated state. One important consequence of the lack of basal venous tone is that vasodilator metabolites that may accumulate in the tissue have little effect on vein.

Because of their walls, veins are much more susceptible to physical influences than are arterioles. Often external compressional forces are an important determinant of venous volume. This is especially true of veins in the skeletal muscle. Very high pressures are developed inside skeletal muscle tissue during contraction and cause venous vessels to collapse. Because veins are venules have one-way valves, the blood displaced from veins during skeletal muscle contraction is forced in the forward direction toward the right site of the heart. In fact, rhythmic skeletal muscle contractions may produce a considerable pumping action, often called the skeletal muscle pump, which helps return blood to the heart during exercise.

Antimicrobials – The Basic Mechanisms

September 8, 2015 Infectious Diseases, Pharmacology No comments , , , , , , , , , ,

The antimicrobials produce their bactericidal or bacteriostatic effects by targeting at certain sites of the pathogens which are susceptible to the antibiotics. Generally, the mechanisms of all antibiotics can be divided into five basic types, or four targets toward which these antibiotics act, including: cell wall synthesis, protein synthesis, nucleic acid synthesis, folate biosynthesis, and cell membrane integrity.


Antibiotics Targeting at Cell Wall Synthesis

Antimicrobials that act on cell wall synthesis can be divided into β-lactams including penicillins, cephalosporins, carbapenems, and monobactams, and non-β-lactams including vancomycin, teicoplanin, telavancin, and bacitracin. The β-lactams antibacterial agents interfere with the transpeptidation reactions that seal the peptide cross links between glycan chains. They do so by interference with the action of the transpeptidase enzymes which carry out this cross-linking. These transpeptidase enzymes we call it in short penicillin-binding proteins (PBPs). Among different species, or even within one strain, the PBPs might have distinctions and vary in their avidity of binding to different β-lactam drugs.Screen Shot 2014-11-07 at 9.44.25 PM

The subtype of β-lactams are based on the chemical structure, the β-lactam ring, which is essential for antibacterial activity. Monobactams have a single β-lactam ring, penicillins and carbapenems have a β-lactam ring fused to a five-member thiazolidine penem ring, and cephalosporins have a β-lactam ring combined with a six-member dihydrothiazine cep hem ring. These differences on the structure affect the pharmacologic properties and spectrum of the specific drug. In general, β-lactam antimicrobials are highly bactericidal, but only to growing bacteria synthesizing new cell walls. One of the key factor that deterring the successful pharmacologic and physical effects of β-lactam is that the drug must penetrate or be transported across the outer membrane of the microbes to get in contact with its receptor, the PBPs.

For instance, penicillin G is active against certain Gram-positive organisms, Gram-negative cocci, and some spirochetes, but lack the activity against Gram-negative bacilli, as the outer membrane of these Gram-negative bacilli prevents passage of penicillin G to the site of action on cell wall synthesis.

For cephalosporins, a agent of a higher generation has a wider spectrum, and in some instances, more quantitative activity (lower MIC) against Gram-negative bacteria. Meanwhile as the Gram-negative spectrum increases, the drug typically loses some of their potency (higher MIC) against Gram-positive bacteria. Note that today there is a fifth-generation cephalosporins, ceftaroline, yes, those guys made it.

β-lactamase inhibitors

These inhibitors are capable of binding irreversibly to β-lactamase enzymes and, in the process, rendering them inactive. There are three β-lactamase inhibitors available, including clavulanic acid, sulbactam, and tazobactam. They also be referred to as suicide inhibitors since they must first be hydrolyzed by a β-lactamase before becoming effective inactivators of the enzyme. Therefore, for infections without β-lactamases, β-lactamase inhibitors are not able to enhance the bactericidal effect.

Glycopeptides

Another type of antimicrobials act against cell wall synthesis is glycopeptides. Each of these antimicrobials inhibits assembly of the linear peptidoglycan molecule by binding directly to the terminal amino acids of the peptide side chains (see the figure above). This effect is the same as with β-lactams: prevention of peptidoglycan cross-linking. Now there are three drug available, including vancomycin, teicoplanin, and telavancin (has additional theoretical advantage of cell membrane activity). Both of vancomycin and teicoplanin are bactericidal, but primarily only against Gram-positive bacteria. Because the both drugs are not absorbed by mouth, they could be used to treat CDI via oral route.


Inhibitors of Protein Synthesis

A variety of antibiotics are within this category of antimicrobials, including aminoglycosides, tetracyclines, chloramphenicol, macrolides, clindamycin, oxazolidinones, and streptogramins.

Aminoglycosides (30S subunit)

Amino glycosides are bactericidal drugs especially useful against many gram-negative rods. Certain ahminoglycosides are used against other organisms (e.g., streptomycin is used in the multi drug therapy of tuberculosis, and gentamicin is used in combination with penicillin G against enterococci). Amino glycosides are named for the amino sugar component of the molecule, which is connected by a glycosidic linkage to other sugar derivatives.

Both inhibition of the initiation complex and misreading of messenger RNA (mRNA) occur, the mechanisms for this class of drug to act, where the former is probably more important for the bactericidal activity of the drug. An initiation complex composed of a streptomycin-treated 30S subunit, a 50S subunit, and mRNA will not function – that is, no peptide bonds are formed, no polysomes are made, and a frozen “streptomycin monosome” results.

Misreading of the triplet codon of mRNA so that the wrong amino acid is inserted into the protein also occurs in streptomycin-treated bacteria. The site of action on the 30S subunit includes both a ribosomal proven and the ribosomal RNA (rRNA).

As a result of inhibition of initiation and misreading, membrane damage occurs and the bacterium dies.

Tetracyclines (30S subunit)

Tetracycline are a family of antibiotics with bacteriostatic activity against a variety of gram-positive and gram-negative bacteria, mycoplasmas, chlamydiae, and rickettsiae. They inhibit protein synthesis by binding to the 30S ribosomal subunit and by blocking the aminoacyl transfer RNA (tRNA) from entering the acceptor site on the ribosome. However, the selective action of tetracycline on bacteria is not at the level of ribosome, because tetracycline in vitro will inhibit protein synthesis equally well in purified ribosomes from both bacterial and human cells. Its selectivity is based on its greatly increased uptake into susceptible bacterial cells compared with human cells.

Chloramphenicol (50S)

Chloramphenicol inhibits protein synthesis by binding to the 50S ribosomal subunit and blocking the action of peptidyltransferase; this prevents the synthesis of new peptide bonds. It inhibits bacterial protein synthesis selectively, because it binds to the catalytic site of the transferase in the 50S bacterial ribosomal subunit but not to the transferase in the 60S human ribosomal subunit.

Chloramphenicol inhibits protein synthesis in the mitochondria of human cells to some extent, since mitochondria have a 50S subunit (mitochondria are thought to have evolved from bacteria). This inhibition may be the cause of the dose-dependent toxicity of chloramphenicol to bone marrow.

Macrolides (50S)

Macrolide’s are a group of bacteriostatic drugs with a wide spectrum of activity. Macrolide’s inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking translocation. They prevent the release of the uncharged tRNA after it has transferred its amino acid to the growing peptide chain. The donor site remains occupied, a new tRNA cannot attach, and protein synthesis stops.

Clindamycin (50S)

The most useful clinical activity of this bacteriostatic drug is against anaerobes, both gram-positive bacteria such as Clostridium perfringens and gram-negative bacteria such as B. fragilis.

Clindamycin binds to the 50S subunit and blocks peptide bond formation by an undetermined mechanism. Its specificity for bacteria arises from its inability to bind to the 60S subunit of human ribosomes.

Linezolid (50S)

Linezolid is useful for the treatment of vancomycin-resistant enterococci, MRSA, and S. epidermis, and penicillin-resistant pneumococci. It is bacteriostatic against enterococci and staphylococci but bactericidal against pneumococci.

Linezolid binds to the 23S ribosomal RNA in the 50S subunit and inhibits protein synthesis, but the precise mechanism is unknown. It appears to block some early step (initiation) in ribosome formation.

Telithromycin (50S)

Telithromycin (Ketek) is the first clinically useful member of the ketolide group of antibiotics. It is similar to the macrocodes in general structure and mode of action but is sufficiently different chemically such that organisms resistant to macrocodes may be sensitive to telithromycin.

Streptogramins (50S)

Streptogramins cause premature release of the growing peptide chain from the 50S ribosomal subunit. The structure and mode of action of streptogramins is different from all other drug that inhibit protein synthesis, and there is no cross-resistance between streptogramins and these other drugs.

Retapamulin (50S)

Raetapamulin is the first clinically available member of a new class of antibiotics called pleuromutilins. These drugs inhibit bacterial protein synthesis by binding to the 23S RNA of the 50S subunit and blocking attachment of the donor tRNA. Retapamulin is a topical antibiotic used in the treatment of skin infections, such as impetigo, caused by S. progenies and methicillin-sensitive S. aureus.


Inhibition of Nucleic Acid Synthesis

This class of drugs include sulfonamides, trimethoprim, fluoroquinolone, flu cytosine, and rifampin. Mechanisms for the inhibition of nucleic acid synthesis include inhibition of precursor synthesis, inhibition of DNA synthesis, and inhibition of mRNA synthesis.

Sulfonamides

Sulfonamides inhibits the precursor synthesis. The mode of action of sulfonamides is to block the synthesis of tetrahydrofolic acid, which is required as a methyl donor in the synthesis of the nucleic acid precursors adenine, guanine, and thymine. Sulfonamides are structural analogues of p-aminobenzoic acid (PABA), which condenses with a pteridine compound to form dihydropteroic acid, a precursor of tetrahydrofolic acid. Sulfonamides compete with PABA for the active site of the enzyme dihydropteroate synthetase. This competitive inhibition can be overcome by an excess of PABA.

The basis of the selective action of sulfonamides on bacteria is that many bacteria synthesize their folic acid from PABA-containing precursors, whereas human cells require preformed folic acid as an exogenous nutrient because they lack the enzymes to synthesize it. Human cells therefore bypass the step at which sulfonamides act, and similarly, bacteria that can use preformed folic acid are similarly resistant to sulfonamides.

Trimethoprim

Trimethoprim also inhibit the production of tetrahydrofolic, whose mechanism belongs to inhibition of precursors synthesis. However, trimethoprim has a different mode of action compared with sulfonamides that it inhibits the enzyme dihydrofolate reductase. Its specificity for bacteria is based on its much greater affinity for bacterial reductase than for the human enzyme.

Fluoroquinolones

Fluoroquinolone’s are bactericidal drugs that block bacterial DNA synthesis by inhibiting DNA gyrase (topoisomerase).

Flucytosine

Flucytosine is an antifungal drug that inhibits DNA synthesis. It is a nucleoside analogue that is metabolized to fluorouracil, which inhibits thymidylate synthetase, thereby limiting the supply of thymidine.

Rifampin

Rifampin belongs to drugs that inhibits synthesis of mRNA. The selective mode of action of rifampin is based on blocking mRNA by bacterial RNA polymerase without affecting the RNA polymerase of human cells. Rifampin is red, and the urine, saliva, and sweat of patients taking rifampin often turn orange; this is disturbing but harmless.


Alteration of Cell Membrane Function

Two sub-categories of mechanisms are involved with alteration of cell membrane function, including: 1.Alteration of bacterial cell membranes; 2.Alteration of fungal cell membranes.

There are few antimicrobial compounds that act on the cell membrane because the structural and chemical similarities of bacterial and human cell membranes make it difficult to provide sufficient selective toxicity.

Polymyxins

Polymyxins are a family of polypeptide antibiotics of which the clinical most useful compound is polymyxin E (colistin). Polymyxins are cyclic peptides composed of 10 amino acids, 6 of which are diaminobutyric acid. The positively charged free amino groups act like a cationic detergent to disrupt the phospholipid structure of the cell membrane.

Daptomycin

Daptomycin is a cyclic lipopeptide that disrupts the cell membranes of gram-positive cocci. It is bactericidal for organisms such as S. aureus, S. epidermis, S. progenies, Enterococcus faecalis, and E. faecium, including methicillin-resistant strains of S. aureus and S. epidermis, vancomycin-resistant strains of E. faecalis and E. faecium.

Amphotericin B

Amphotericin B disrupts the cell membrane of fungi because of its affinity for ergosterol, a component of fungal membranes but not of bacterial or human cell membranes.

Nystatin

Nystatin is another polyene antifungal agent, which, because of its toxicity, is used topically for infections caused by the yeast Candida.

Terbinafine

Terbinafine blocks ergosterol synthesis by inhibiting squalene epoxidase.

Azoles (Fluconzole, Ketoconazole, Voriconazole, etc.)

They act by inhibiting ergosterol synthesis. The block cytochrome P-450-dependent demethylation of lanosterol, the precursor of ergosterol.


Others

Isoniazid (prodrug probably, see below)

Isoniazid is a bactericidal drug highly specific for Mycobacterium tuberculosis. Isoniazid inhibits mycolic acid synthesis, which explains why it is specific for mycobacteria and relatively nontoxic for humans. The drug inhibits a reductase required for the synthesis of the long-chain fatty acids called mycolic acids that are an essential constituent of mycobacterial cell walls. The active drug is probably a metabolite of isoniazid formed by the action of catalase peroxidase because deletion of the gene for these enzymes results in resistance to the drug.

Metronidazole (prodrug)

Metronidazole is bactericidal against aerobic bacteria (also effective against certain protozoa such as Giardia and Trichomonas). Metronidazole is a prodrug that is activated to the active compound within anaerobic bacteria by ferredoxin-mediated reduction of its nitro group. This drug has two possible mechanisms of action, and it is unclear which is the more important. The first, which explains its specificity for anaerobes, is its ability to act as an electron sink. By accepting electrons, the drug deprives the organism of required reducing power. In addition, when electrons are acquired, the drug ring is cleaved and a toxic intermediate is formed that damages DNA. The precise nature of the intermediate and its action is unknown.

The second mode of action of metronidazole relates to its ability to inhibit DNA synthesis. The drug binds to DNA and causes strand breakage, which prevents its proper functioning as a template for DNA polymerase.

Ethambutol

Ethambutol is a bacteriostatic drug active against M. tuberculosis and many of the atypical mycobacteria. It is thought to act by inhibiting the synthesis of arabinogalactan, which functions as a link between the mycolic acids and the peptidoglycan of the organism.

Griseofulvin

Griseofulvin is an antifungal drug that is useful in the treatment of hair and nail infections caused by dermatophytes. It binds to tubulin in microtubules and may act by preventing formation of the mitotic spindle.

Pentamidine

Pentamidine is active against fungi and protozoa. It hinibits DNA synthesis by an unknown mechanism.