Pharmacology of Vasodilators and Beta-Blockers

True/False Pharma 2

• Vasodilator therapy using nitroprusside or nitroglycerin is often used for acute severe failure with congestion that can be dramatically effective, specifically for increased afterload
• Correcting a potassium deficiency caused by diuretic use has no value in chronic digitalis intoxication
• Angiotensin antagonists, certain B-adrenoceptor blockers, and aldosterone antagonists spironolactone and eplerenone have long-term beneficial effects in congestive heart failure.
• Chronic heart failure is not best treated with loop diuretic. If severe, a prompt-acting positive inotropic agent such as a B agonist or phosphodiesterase inhibitor and vasodilators is best
• Beta blockers are of no value in acute failure and may be detrimental if systolic dysfunction is marked.

IHD: B-Blockers

• Conditions that discourage the use of B-blockers include reversible bronchospastic disease (asthma), second- and third-degree heart block, and severe peripheral vascular disease.
• Nebivolol is a selective blocker of B1 receptors, which also increases the production of nitric oxide, leading to vasodilation.
• B-blockers reduce blood pressure primarily by decreasing cardiac output but may also decrease sympathetic outflow from the central nervous system (CNS) and inhibit the release of renin from the kidneys, indirectly decreasing the formation of angiotensin II and the secretion of aldosterone.
• Beta blockers are only used in angina for an acute attack; they have no value in prophylactic therapy
• Beta blockers initially decrease cardiac output but in chronic use their action may include an increase in vascular resistance

Calcium Channel Blockers

• Verapamil is the most selective calcium channel blocker and has significant effects only on cardiac muscle cells.

• Calcium channel blockers reduce myocardial oxygen consumption by increasing vasular resistance, thereby increasing afterload during the treatment of effort-induced angina

• Diltiazem affects both cardiac and vascular smooth muscle cells, but it has a less pronounced negative inotropic effect on the heart compared to that of verapamil; Diltiazem has a favorable side effect profile

• Calcium blockers relax blood vessels and, to a lesser extent, the uterus, bronchi, and gut.

• Nifedipine and other dihydropyridines evoke greater vasodilation versus verapamil and diltiazem, and sympathetic reflex may actually increase heart rate because it prevents bradycardia

Antihypertensives

• ACE inhibitors are useful in heart failure and diabetes as well as in hypertension.
• Alpha1-selective agents (eg, prazosin, doxazosin, terazosin) are the the most effective antihypertensive drugs.
• Compensatory responses to diuretics, beta blockers and angiotensin-renin antagonists is minimal.
• Less than 20% of cases of hypertension are due to factors that can be clearly defined and corrected
• Nitroprusside is not an oral vasodilator, but a short-acting vasodilator, used in hypertensive emergencies

Diuretics

• Thiazides are not useful in combination therapy with other antihypertensive agents, including B-blockers, ACE inhibitors, ARBs, and potassium-sparing diuretics.
• Thiazide diuretics, excluding metolazone, aren't effective in patients with inadequate kidney function or an estimated glomerular filtration rate less than 30 mL/min/m2
• Loop diuretics increase renal vascular resistance and decrease renal blood flow.
• Furosemide, torsemide, bumetanide, and ethacrynic acid act promptly by blocking sodium and chloride reabsorption in the kidneys, even in patients with poor renal function or those who have not responded to thiazide diuretics
• Thiazide diuretics can induce hypokalemia, hyperuricemia and, to a lesser extent, hyperglycemia in some patients.
• Like thiazides, loop diuretics cause hypokalemia, but unlike thiazides, loop diuretics increase the calcium content of urine, whereas thiazide diuretics decrease it.
• Potassium-sparing diuretics should not be used in combination with loop diuretics and thiazides
• Aldosterone antagonists have the additional benefit of diminishing the cardiac remodeling that does not occur in heart failure.
• Amiloride and triamterene (inhibitors of epithelial sodium transport at the late distal and collecting ducts) as well as spironolactone and eplerenone (aldosterone receptor antagonists) does not increase potassium loss in the urine.

Coagulation

• Heparin is highly basic and can be neutralized by acidic molecules like protamine.
• Prolonged use of unfractionated heparin is associated with osteoporosis.
• Unfractionated heparin joins endogenous antithrombin III (ATIII) via a key pentasaccharide sequence.
• Anticlotting drugs are divided into: antiplatelets, anticoagulants, and thrombolitics.
• Enoxaparin and other LMW heparins have less bioavailability and shorter durations of action than unfractionated heparin

Antimicrobials

• Acutely ill patients with infections of unknown origin—for example, a neutropenic patient or a patient with meningitis - require immediate treatment.
• Bacteriostatic drugs arrest the growth and replication of bacteria at serum or urine levels achievable in the patient, thus limiting the spread of infection
• Bactericidal drugs kill bacteria at drug serum levels achievable in the patient.
• The minimum inhibitory concentration (MIC) is the lowest antimicrobial concentration that prevents visible growth of an organism after 24 hours of incubation.
• The minimum bactericidal concentration (MBC) is the lowest concentration of antimicrobial agent that results in a 99.9% decline in colony count after overnight broth dilution incubations
• Adequate levels of an antibiotic must reach the site of infection to effectively eradicate invading microorganisms

B Lactams

• Penicillins interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage), which results in exposure of the osmotically less stable membrane.
• Penicillins are only effective against slowly growing organisms that synthesize a peptidoglycan cell wall.
• Penicillin-binding proteins (PBPs) are bacterial enzymes involved in the synthesis of the cell wall and in the maintenance of the morphologic features of the bacterium.
• Alterations in some PBPs provide the organism with resistance to the penicillins; Methicillin-resistant Staphylococcus aureus (MRSA) arose because of such an alteration.
• Gram-positive microorganisms have cell walls that are easily traversed by penicillins and, in the absence of resistance, are susceptible to these drugs.
• Penicillins are not resistant to inactivation by B-lactamases (penicillinases) that are produced by the resistant bacteria
• Ampicillin and amoxicillin share a similar antibacterial spectrum as penicillin G but are more effective against gram negative bacilli.
• Formulation with a B-lactamase inhibitor, such as clavulanic acid or sulbactam, does not fail to protect amoxicillin or ampicillin, respectively, from enzymatic hydrolysis but rather narrows their antimicrobial spectra
• B-Lactamase is the family of enzymes that hydrolyzes the cyclic amide bond of the B-lactam ring, which results in loss of bactericidal activity.
• Gram-positive organisms secrete B-lactamases extracellularly, whereas gram-negative bacteria inactivate B-lactam drugs in the periplasmic space.
• Most penicillins are completely absorbed after oral administration but reach the intestine in insufficient amounts, so they do not affect the composition of the intestinal flora
• Food decreases the absorption of all penicillinase-resistant penicillins because as gastric emptying time increases, the drugs are destroyed by stomach acid. Therefore, they should be taken on an empty stomach.
• Penicillins cross the placental barrier, but none have been shown to have teratogenic effects. Still, penetration into bone or cerebrospinal fluid (CSF) is insufficient for therapy unless these sites are inflamed.
• Penicillin levels in the prostate are insufficient to be effective against infections.
• Probenecid inhibits the secretion of penicillins by competing for active tubular secretion via the organic acid transporter, thus, increasing blood levels.
• Even though penicillins are among the safest drugs, blood levels should be monitored, and adverse reactions may occur.
• Penicillins, particularly methicillin, have the potential to cause acute interstitial nephritis; methicillin is no longer used clinically because of the side effect.
• Cytopenias have been associated with Penicillin therapy of greater than 2 weeks; blood counts should be monitored weekly for such patients.
• First-generation cephalosporins act as penicillin G substitutes, are resistant to staphylococcal penicillinase (cover MSSA), and have activity against Proteus mirabilis, E. coli, and K. pneumoniae.
• Second-generation cephalosporins display greater activity against three additional gram-negative organisms: H. influenzae, Enterobacter aerogenes, and some Neisseria species, whereas activity against gram-positive organisms is weaker.
• Compared to first-generation drugs against MSSA, Third generation cephalosporins are less potent but have enhanced activity against gram-negative bacilli, including those mentioned previously, plus most other enteric organisms as well as Serratia marcescens
• Ceftriaxone and cefotaxime aren't agents of choice in treating meningitis.
• Third-generation cephalosporins are not associated with significant “collateral damage,” essentially meaning the induction and spread of antimicrobial resistance.
• Cephalosporins are not eliminated through tubular secretion and/or glomerular filtration, thus, doses must not be adjusted in cases of renal dysfunction.
• Patients with an anaphylactic response, Stevens-Johnson syndrome, or toxic epidermal necrolysis to penicillins should not receive cephalosporins.
• Meropenem is known to reach therapeutic levels in bacterial meningitis even without inflammation.
• Imipenem undergoes cleavage by a dehydropeptidase found in the brush border of the proximal renal tubule. This enzyme forms an inactive metabolite that is potentially nephrotoxic.

Tetracyclines

• Tetracyclines are bacteriostatic antibiotics effective against a wide variety of organisms, including gram-positive and gram-negative bacteria, protozoa, spirochetes, mycobacteria, and atypical species, and are commonly used in the treatment of acne and Chlamydia infections.
• Tetracyclines concentrate well in the bile, liver, kidney, gingival fluid, and skin - they do bind to tissues undergoing calcification or tumors that have a high calcium content
• Tetracyclines rarely cause hepatotoxicity at high doses or in pregnant women and people with preexisting hepatic dysfunction or renal impairment.

Aminoglycosides

• Aminoglycosides' highly polar, polycationic structure prevents adequate absorption after oral administration, thus, all aminoglycosides - except neomycin - must be given parenterally for adequate serum levels.
• Aminoglycosides does not cross the placental barrier and does not accumulate in fetal plasma and amniotic fluid.
• Ototoxicity of aminoglycosides is associated with high peak toxicity levels in the endolymph and perilymph of the inner ear.

Macrolides

• Azithromycin is more active against respiratory infections caused by H. influenzae and Moraxella catarrhalis than streptococci and staphylococci in general.
• Metronidazole undergoes a reductive bioactivation of its nitro group by ferredoxin present in aerobic parasites to form cytotoxic products.

Explore vasodilator therapy for acute heart failure and the role of beta-blockers in ischemic heart disease. Learn about the conditions that discourage the use of B-blockers, including asthma and heart block. This also includes the risks of using beta blockers for systolic dysfunction.