PHARM CH.11 - ANTIHYPERTENSIVE AGENTS

What classes of drugs act specifically on the renin-angiotensin system (3 specific)

1. ACE inhibitors 2. competitive inhibitors of angiotensin at its receptors, including losartan and other nonpeptide antagonists 3. aliskiren, an orally active renin antagonist (aldosterone receptor inhibitors, e.g. spironolactone) (beta blockers reduce renin secretion)

What are the 4 major classes of antihypertensive drugs in terms of their site of action?

1. diuretics - lower BP by depleting the body of sodium and reducing blood volume 2. sympathoplegic agents - lower BP by reducing PVR, inhibiting cardiac function, and increasing venous pooling in capacitance vessels (site = sympathetic reflex arc) 3. Direct vasodilators - reduce pressure by relaxing vascular smooth muscle, thus dilating resistance vessels and increasing capacitance 4. Agents that block production or action of angiotensin - reduce PVR and blood volume

What are the 4 mechanisms by which vasodilators operate?(examplesofeach)

1. release of nitric oxide from drug or endothelium (nitroprusside, hydralazine, nitrates, histamine, acetylcholine) 2. reduction of calcium influx (verapamil, diltiazem, nifedipine) 3. hyperpolarization of cell membranes through opening of K channels (minoxidil, diazoxide) 4. activation of dopamine receptors (fenoldopam) ===================== oral vasodilators = hydralazine, minoxidil = use for longterm outpt therapy parenteral vasodilators = nitroprusside, fenoldopam = used for hypertensive emergencies calcium channel blockers are used in both instances nitrates are used mainly in ischemic heart disease, but sometimes in hypertensive emergencies -> All the vasodilators that are useful in hypertension relax smooth muscle of arterioles, thereby decreasing systemic vascular resistance. Sodium nitroprusside and the nitrates also relax veins. Decreased arterial resistance and decreased mean arterial blood pressure elicit compensatory responses, mediated by baroreceptors and the sympathetic nervous system -> Because sympathetic reflexes are intact, vasodilator therapy does not cause orthostatic hypotension or sexual dysfunction.

NHANES found that only _____ of Americans w/ HTN had adequate blood pressure control.

50%

Angiotensin receptor blocking agents:

Angiotensin II type 1 (AT1) receptor losartan, valsartan, azilsartan, candesartan, eprosartan, irbesartan, olmesartan, temisartan no effect on bradykinin metabolism -> more selective blockers of angiotensin than ACE inhibitors potential for more complete inhibition of angiotensin action compared with ACE inhibitors because there are enzymes other than ACE that are capable of generating angiotensin II provide benefits similar to those of ACE inhibitors in pts w/ heart failure and CKD adverse effects similar to ACE inhibitors, including hazard during pregnancy Angiotensin receptor-blocking drugs are most commonly used in patients who have had adverse reactions to ACE inhibitors.

Hydraulic equation;

BP = CO x PVR where BP = blood pressure CO= cardiac output PVR = peripheral vascular resistance

Renal control of blood pressure:

By controlling blood volume, the kidney is primarily responsible for long-term blood pressure control. A reduction in renal perfusion pressure causes intrarenal redistribution of blood flow and increased reabsorption of salt and water. In addition, decreased pressure in renal arterioles as well as sympathetic neural activity (via β adrenoceptors) stimulates production of renin, which increases production of angiotensin II. Angiotensin II causes (1) direct constriction of resistance vessels and (2) stimulation of aldosterone synthesis in the adrenal cortex, which increases renal sodium absorption and intravascular blood volume. Vasopressin (ADH) released from the posterior pituitary gland also plays a role in maintenance of blood pressure through its ability to regulate water reabsorption by the kidney

How does site of action for subclasses of sympathoplegic drugs contribute to exhibiting different patterns of potential toxicity?

Drugs that lower blood pressure by actions on the central nervous system tend to cause sedation and mental depression and may produce disturbances of sleep, including nightmares. Drugs that act by inhibiting transmission through autonomic ganglia (ganglion blockers) produce toxicity from inhibition of parasympathetic regulation, in addition to profound sympathetic blockade and are no longer used. Drugs that act chiefly by reducing release of norepinephrine from sympathetic nerve endings cause effects that are similar to those of surgical sympathectomy, including inhibition of ejaculation, and hypotension that is increased by upright posture and after exercise. Drugs that block postsynaptic adrenoceptors produce a more selective spectrum of effects depending on the class of receptor to which they bind.

Propranolol: What makes beta blocking agents useful w/ severe HTN? How does propranolol reduce blood pressure? toxicity? Withdrawal?

In severe hypertension, β blockers are especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators. decreases BP primarily as a result of decreased cardiac output and inhibition of renin production by catecholamines at B1 receptors (might also act on peripheral presynaptic β adrenoceptors to reduce sympathetic vasoconstrictor nerve activity.) propranolol produces a significant reduction in blood pressure without prominent postural hypotension. Propranolol dosage is guided by resting bradycardia and reduction in HR during exercise Toxicity: predictable extensions of the β1-blocking action occur in patients with bradycardia or cardiac conduction disease, and those of the β2-blocking action occur in patients with asthma, peripheral vascular insufficiency, and diabetes. Withdrawal: - nervousness, tachycardia, increased intensity of angina, increase BP (MI has been reported)

Polypharmacy in resistant HTN - what is the rationale? (3 points)

Monotherapy of hypertension (treatment with a single drug) is desirable because compliance is likely to be better and the cost is lower, and because in some cases adverse effects are fewer. However, most patients with hypertension require two or more drugs acting by different mechanisms (polypharmacy) 1. most drugs evoke compensatory regulatory mechanisms for maintaining blood pressure, which may markedly limit their effect. -> For example, vasodilators such as hydralazine cause a significant decrease in peripheral vascular resistance, but evoke a strong compensatory tachycardia and salt and water retention that are capable of almost completely reversing their effect. The addition of a β blocker prevents the tachycardia; addition of a diuretic (eg, hydrochlorothiazide) prevents the salt and water retention. In effect, all three drugs increase the sensitivity of the cardiovascular system to each other's actions. 2. some drugs have only modest maximum efficacy but reduction of long-term morbidity mandates their use. Many studies of angiotensin-converting enzyme (ACE) inhibitors report a maximal lowering of blood pressure of less than 10 mm Hg. ACE inhibitors have important long-term benefits in preventing or reducing renal disease in diabetic persons and in reduction of heart failure. 3. the toxicity of some effective drugs prevents their use at maximally effective doses In practice, when hypertension does not respond adequately to a regimen of one drug, a second drug from a different class with a different mechanism of action and different pattern of toxicity is added. If the response is still inadequate and compliance is known to be good, a third drug should be added. If three drugs (usually including a diuretic) are inadequate, other causes of resistant hypertension should be considered. Two promising treatments that are still under investigation, particularly for patients with advanced kidney disease, are renal denervation and carotid barostimulation.

Management of hypertensive emergencies: What is malignant HTN? What is the classic feature? What is the goal of treatment?

Most frequently, hypertensive emergencies occur in patients whose hypertension is severe and poorly controlled and in those who suddenly discontinue antihypertensive medications Hypertensive emergencies include hypertension associated with vascular damage (termed malignant hypertension) and hypertension associated with hemodynamic complications such as heart failure, stroke, or dissecting aortic aneurysm. The underlying pathologic process in malignant hypertension is a progressive arteriopathy with inflammation and necrosis of arterioles. Vascular lesions occur in the kidney, which releases renin, which in turn stimulates production of angiotensin and aldosterone, which further increase blood pressure. Hypertensive encephalopathy is a classic feature of malignant hypertension. Its clinical presentation consists of severe headache, mental confusion, and apprehension. Blurred vision, nausea and vomiting, and focal neurologic deficits are common. If untreated, the syndrome may progress over a period of 12-48 hours to convulsions, stupor, coma, and even death. Parenteral antihypertensive medications are used to lower blood pressure rapidly (within a few hours); as soon as reasonable blood pressure control is achieved, oral antihypertensive therapy should be substituted because this allows smoother long-term management of hypertension. The goal of treatment in the first few hours or days is not complete normalization of blood pressure because chronic hypertension is associated with autoregulatory changes in cerebral blood flow. Thus, rapid normalization of blood pressure may lead to cerebral hypoperfusion and brain injury. Rather, blood pressure should be lowered by about 25%, maintaining diastolic blood pressure at no less than 100-110 mm Hg. Subsequently, blood pressure can be reduced to normal levels using oral medications over several weeks. The parenteral drugs used to treat hypertensive emergencies include sodium nitroprusside, nitroglycerin, labetalol, calcium channel blockers, fenoldopam, and hydralazine. Esmolol is often used to manage intraoperative and postoperative hypertension. Diuretics such as furosemide are administered to prevent the volume expansion that typically occurs during administration of powerful vasodilators.

Renin-Aldosterone-Angiotensin system: What 3 functions does angiotensin II perform? Angiotensin III?

Renin release from the kidney cortex is stimulated by reduced renal arterial pressure, sympathetic neural stimulation, and reduced sodium delivery or increased sodium concentration at the distal renal tubule Renin acts upon angiotensinogen to yield the inactive precursor decapeptide angiotensin I. Angiotensin I is then converted, primarily by endothelial ACE, to the arterial vasoconstrictor octapeptide angiotensin II, which is in turn converted in the adrenal gland to angiotensin III. Angiotensin II has vasoconstrictor, sodium-retaining activity, and stimulates aldosterone release. Angiotensin III also stimulates aldosterone release.

Centrally acting sympathoplegic drugs - mechanism of action - how do centrally acting sympathoplegic drugs different from those that act directly on peripheral sympathetics? What are the 2 most common and what is their mechanism? How do they differ in hemodynamic effect? selectivity for receptors of both? What 2 drugs share the same receptor as clonidine (but are rarely used clincially?)

These agents reduce sympathetic outflow from vasomotor centers in the brain stem but allow these centers to retain or even increase their sensitivity to baroreceptor control. Accordingly, the antihypertensive and toxic actions of these drugs are generally less dependent on posture than are the effects of drugs that act directly on peripheral sympathetic neurons. Methyldopa: analog of L-dopa, converted to α-methyldopamine and α-methylnorepinephrine; this pathway directly parallels the synthesis of norepinephrine from dopa -> Alpha-methylnorepinephrine is stored in adrenergic nerve vesicles, where it stoichiometrically replaces norepinephrine -> α-methylnorepinephrine released is an effective agonist at the α adrenoceptors that mediate peripheral sympathetic constriction of arterioles and venules. Methyldopa's antihypertensive action appears to be due to stimulation of central α adrenoceptors by α-methylnorepinephrine or α-methyldopamine. -> lowers blood pressure chiefly by reducing peripheral vascular resistance, with a variable reduction in heart rate and cardiac output. Clonidine: discovered in testing it as nasal decongestant - pressor response due to direct stimulation of alpha-adrenoceptors in arterioles followed by hypotension (partial agonist of alpha receptors.- inhibits pressor effects of other alpha-agonists) -> hypotensive effect due to direct stimulation of alpha-adrenoceptors in the medulla of the brain -> Clonidine reduces sympathetic and increases parasympathetic tone, resulting in blood pressure lowering and bradycardia. The reduction in pressure is accompanied by a decrease in circulating catecholamine levels. These observations suggest that clonidine sensitizes brain stem vasomotor centers to inhibition by baroreflexes. -> clonidine also binds to a nonadrenoceptor site, the imidazoline receptor, which may also mediate antihypertensive effects Clonidine and α-methylnorepinephrine bind more tightly to α2 than to α1 adrenoceptors Methyldopa and clonidine produce slightly different hemodynamic effects: clonidine lowers heart rate and cardiac output more than does methyldopa. This difference suggests that these two drugs do not have identical sites of action. Guanabenz and guanfacine are centrally active antihypertensive drugs that share the central α-adrenoceptor-stimulating effects of clonidine. They do not appear to offer any advantages over clonidine and are rarely used. **In summary, these agents actually cause vasoconstriction/alpha stimulation peripherally, but their overall antihypertensive effect comes from stimulation of alpha receptors in the brain stem**

Resperidine - mechanism and toxicity - what 2 conditions are a contraindication for resperine?

alkaloid extracted from the roots of an Indian plant, Rauwolfia serpentina At present, it is rarely used owing to its adverse effects. mechanism: resperine blocks the ability of aminergic transmitter vesicles to take up and store biogenic amines (interfering w/ VMAT) *irreversible* -> results in depletion of norepinephrine, dopamine, and serotonin in both central and peripheral neurons Toxicity: - Most of the unwanted effects of reserpine result from actions on the brain or gastrointestinal tract. - Reserpine readily enters the brain, and depletion of cerebral amine stores causes sedation, lassitude, nightmares, and severe mental depression, extrapyramidal effects resembling Parkinson's disease, probably as a result of dopamine depletion in the corpus striatum. - mild diarrhea and gastrointestinal cramps and increases gastric acid secretion. **Pts with a hx of mental depression should not receive reserpine **The drug should not be given to patients with a history of peptic ulcer.

When are sympathoplegic agents most effective?

all of the agents that lower blood pressure by altering sympathetic function can elicit compensatory effects through mechanisms that are not dependent on adrenergic nerves. Thus, the antihypertensive effect of any of these agents used alone may be limited by retention of sodium by the kidney and expansion of blood volume. For this reason, sympathoplegic antihypertensive drugs are most effective when used concomitantly with a diuretic.

calcium channel blockers: mechanism? what drugs fit into this category? How do they compare in terms of efficacy?

antianginal, antiarrhythmic, and antihypertensive effects inhibits calcium influx into arterial smooth muscle cells verapamil, diltiazem, dihydropyridine family (amlodopine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, clevidipine) Nifedipine and the other dihydropyridine agents are more selective as vasodilators and have less cardiac depressant effect than verapamil and diltiazem. Verapamil = greatest cardiac depressant effect (decreases HR and CO) recommended that short-acting oral dihydropyridines not be used for hypertension. Sustained-release calcium blockers or calcium blockers with long half-lives provide smoother blood pressure control and are more appropriate for treatment of chronic hypertension.

Diagnosis of HTN: How does risk differ among populations? (race, gender)

based on repeated, reproducible measurements of elevated blood pressure. the diagnosis of hypertension depends on measurement of blood pressure and not on symptoms reported by the patient. Starting at 115/75 mm Hg, cardiovascular disease risk doubles with each increment of 20/10 mm Hg throughout the blood pressure range. The risk of end-organ damage at any level of blood pressure or age is greater in African Americans and relatively less in premenopausal women than in men. Other positive risk factors include smoking; metabolic syndrome, including obesity, dyslipidemia, and diabetes; manifestations of end-organ damage at the time of diagnosis; and a family history of cardiovascular disease.

Esmolol for tx of HTN:

beta-1 selective blocker that is rapidly metabolized via hydrolysis by RBC esterases short half life, given IV (loading dose) used for management of intraportative and postoperative HTN and hypertensive emergencies, particularly when hypertension is associated with tachycardia or when there is concern about toxicity such as aggravation of severe heart failure

labetolol, carvedilol, and nebivolol as tx for HTN- in what condition is each most useful?

both beta-blocking and vasodilating effects all 3 prepared as racemic mixture Labetolol: Blood pressure is lowered by reduction of systemic vascular resistance (via α blockade) without significant alteration in heart rate or cardiac output. Because of its combined α- and β-blocking activity, labetalol is useful in treating the hypertension of pheochromocytoma and hypertensive emergencies. Carvedilol: particularly useful in pts with both heart failure and hypertension Nebivolol: most selective β1-selective blocker with vasodilating properties; increase in endothelial release of NO via induction of endothelial nitric oxide synthase

metoprolol and atenolol as tx for HTN: how do they compare in terms of efficacy?

cardioselective (most widely used beta blockers) advantageous in treating hypertensive patients who also suffer from asthma, diabetes, or peripheral vascular disease. Metoprolol is extensively metabolized by CYP2D6 with high first-pass metabolism. Sustained-release metoprolol is effective in reducing mortality from heart failure and is particularly useful in patients with hypertension and heart failure. ------------------ Atenolol - less extensively metabolized, excreted primarily in urne - less effective than metropolol in preventing complications (only given as once daily pill)

Diuretics - mechanism of action and hemodynamic effects: what effect does sodium have on vessels? what compensatory mechanisms warrant the addition of a diuretic for pharmacologic management? when are the different diuretics warranted? (thiazide diuretics/chlorthalidone, furosemide, potassium-sparing diuretics (i.e, spironolactone)? )

deplete body sodium stores Initially, diuretics reduce BP by reducing blood volume and therefore, cardiac output - PVR may increase. After 6-8 wks, cardiac output returns to nl while PVR declines. Sodium is believed to contribute to vascular resistance by increasing vessel stiffness and neural reactivity (altered sodium-calcium exchange) -> these effects are reversed by diuretics and dietary sodium restriction in more severe HTN, diuretics are used in combo w/ sympathoplegic and vasodilator drugs to control tendency toward sodium retention caused by these agents Vascular responsiveness—ie, the ability to either constrict or dilate—is diminished by sympathoplegic and vasodilator drugs, so that the vasculature behaves like an inflexible tube. As a consequence, blood pressure becomes exquisitely sensitive to blood volume. Thiazide diuretics are appropriate for most patients with mild or moderate hypertension and normal renal and cardiac function -> the use of chlorthalidone in preference to others is supported by evidence of improved 24-hour blood pressure control and reduced cardiovascular events (longer duration of action compared to HCTZ) -> furosemide = more powerful; necessary in severe HTN, renal insufficiency, and in cardiac failure/cirrhosiss (sodium retention marked) -> Potassium-sparing diuretics useful to avoid excess K depletion + to enhance the natriuteric effects of diuretics (Aldosterone receptor antagonists - favorable effect on cardiac function in people with heart failure)

Diagnosis and management of HTN:

determine if secondary cause is present that can be treated w/ definitive surgical procedures Persistence of hypertension, particularly in persons with mild elevation of blood pressure, should be established by finding an elevated blood pressure on at least three different office visits. Ambulatory blood pressure monitoring may be the best predictor of risk and therefore of need for therapy in mild hypertension, and is recommended for initial evaluation of all patients in the guidelines of some countries. Isolated systolic hypertension and hypertension in the elderly also benefit from therapy. Education about the natural history of hypertension and the importance of treatment adherence as well as potential adverse effects of drugs is essential. Obesity should be treated and drugs that increase blood pressure (sympathomimetic decongestants, nonsteroidal anti-inflammatory drugs, oral contraceptives, and some herbal medications) should be eliminated if possible. Follow-up visits should be frequent enough to convince the patient that the physician thinks the illness is serious. With each follow-up visit, the importance of treatment should be reinforced and questions concerning dosing or side effects of medication encouraged. Other factors that may improve compliance are simplifying dosing regimens and having the patient monitor blood pressure at home. Assessment of blood pressure during office visits should include measurement of recumbent, sitting, and standing pressures. An attempt should be made to normalize blood pressure in the posture or activity level that is customary for the patient. Target = systolic 120 Systolic hypertension (> 150 mm Hg in the presence of normal diastolic blood pressure) is a strong cardiovascular risk factor in people older than 60 years of age and should be treated. noncompliance, excessive sodium intake, and inadeq diuretic therapy + such drugs like antidepressants, NSAIDs, OTC sympathomimetics, abuse of stimulants, or excessive doses of caffeine and oral contraceptives can interfere w/ actions of antihypertensive drugs

Hydralazine: How does it cause vasodilation? In what combo is hydralazine effective in heart failure? What population sees greater first pass metabolism and less antihypertensive benefit? Toxicity (particularly in patients w/ what condition)? What kind of syndrome may present in pts with slow acetylators?

dilates arterioles but not veins causes release of nitric oxide The combination of hydralazine with nitrates is effective in heart failure and should be considered in patients with both hypertension and heart failure, especially in African-American patients. rapidly metabolized by liver during first pass -> bioavailability low It is metabolized in part by acetylation at a rate that appears to be bimodally distributed in the population. As a consequence, rapid acetylators have greater first-pass metabolism, lower blood levels, and less antihypertensive benefit from a given dose than do slow acetylators. vascular effects persist longer than do blood concentrations, possibly due to avid binding to vascular tissue. Toxicity: HA, nausea, anorexia, palpitations, sweating, flushing -> in pts with ischemic heart disease, reflex tachycardia and sympathetic stimulation may provoke angina or ischemic arrhythmias In pts with slow acetylation, a syndrome characterized by arthralgia, myalgia, skin rashes, and fever that resembles lupus erythematosus may present.

Ganglion-blocking agents - mechanism? adverse effects associated?

drugs that block activation of postganglionic autonomic neurons by acetylcholine Most such drugs are no longer available clinically because of intolerable toxicities related to their primary action Ganglion blockers competitively block nicotinic cholinoceptors on postganglionic neurons in both sympathetic and parasympathetic ganglia. In addition, these drugs may directly block the nicotinic acetylcholine channel, in the same fashion as neuromuscular nicotinic blockers Adverse effects: both sympathoplegia (excessive orthostatic hypotension and sexual dysfunction) and parasympathoplegia (constipation, urinary retention, precipitation of glaucoma, blurred vision, dry mouth, etc).

ACE Inhibitors- mechanism by which they achieve hypotensive activity, drugs in this class, what advantage do these drugs offer over direct vasodilators? ACE inhibitors have a particularly useful role in treating patients w/ (4) toxicity (what sx can present from angiotensin II inhibiting effect (3) versus bradykinin effect (3) ?) In what population are ACE inhibitors contraindicated? Important drug interactions (2)

inhibit the converting enzyme peptidyl dipeptidase that hydrolyzes angiotensin I to angiotensin II and (under the name plasma kininase) inactivates bradykinin, a potent vasodilator that works at least in part by stimulating release of nitric oxide and prostacyclin. The hypotensive activity of captopril results both from an inhibitory action on the renin-angiotensin system and a stimulating action on the kallikrein-kinin system captopril, Enalapril is an oral prodrug that is converted by hydrolysis to a converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril (only for intravenous use, primarily for hypertensive emergencies) Lisinopril is a lysine derivative of enalaprilat. Benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril -> All are converted to active agents by hydrolysis primarily in the liver Angiotensin II inhibitors lower blood pressure principally by decreasing peripheral vascular resistance. Cardiac output and heart rate are not significantly changed. Unlike direct vasodilators, these agents do not result in reflex sympathetic activation and can be used safely in persons with ischemic heart disease. ACE inhibitors have a particularly useful role in treating patients w/ chronic kidney disease because they diminish proteinuria and stabilize renal function -> particularly valuable in diabetes (now recommended even in the absence of HTN) -> probably result from decreased glomerular efferent arteriolar resistance and a resulting reduction of intraglomerular capillary pressure. Also particularly useful in tx of heart failure and after MI doses of these drugs should be reduced in patients with renal insufficiency Toxicity: Severe hypotension can occur after initial doses of any ACE inhibitor in patients who are hypovolemic as a result of diuretics, salt restriction, or gastrointestinal fluid loss. acute renal failure (particularly in patients with bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney), hyperkalemia, dry cough sometimes accompanied by wheezing, and angioedema. Hyperkalemia is more likely to occur in patients with renal insufficiency or diabetes. Bradykinin and substance P seem to be responsible for the cough and angioedema seen with ACE inhibition. Contraindicated in 2nd and 3rd trimester of pregnancy - risk of fetal hypotension, anuria, and renal failure, fetal malformation, death (increased teratogenic risk) Drug interactions: - potassium supplements & potassium-sparing diuretics -> riks of hyperkalemia - NSAIDs - impair hypotensive effect of ACE inhibitors by blocking bradykinin-mediated vasodilation

Outpt therapy of HTN: how does concomitant disease influence selection of antihypertensive drugs? Race?

initial step = nonpharmacologic -> sodium restriction -> diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat, and moderation of alcohol intake - weight reduction - regular exercise mild HTN pharmacological management -> often a single drug -> diuretics, ACE inhibitors, angiotensin receptor blockers, calcium channel blockers (beta blockers not recommended as first-line tx alone) moderate/severe-> 2+ drugs The presence of concomitant disease should influence selection of antihypertensive drugs because two diseases may benefit from a single drug. - drugs that inhibit the renin-angiotensin system are particularly useful in patients with diabetes or evidence of chronic kidney disease with proteinuria. - Beta blockers or calcium channel blockers are useful in patients who also have angina; -diuretics, ACE inhibitors, angiotensin receptor blockers, β blockers, or hydralazine combined with nitrates in patients who also have heart failure; -α1 blockers in men who have benign prostatic hyperplasia. Race may also affect drug selection: African Americans respond better on average to diuretics and calcium channel blockers than to β blockers and ACE inhibitors. Chinese patients are more sensitive to the effects of β blockers and may require lower doses. If a fourth drug is needed, a sympathoplegic agent such as a β blocker or clonidine should be considered. In the USA, fixed-dose drug combinations are available.

Diazoxide - mechanism what clinical use is it used for today? Toxicity?

long acting K channel opener - causes hyperpolarization in smooth muscle and pancreatic B cells at present, used orally for tx of hypoglycemia in hyperinsulinism (Diazoxide inhibits insulin release from pancreas by opening K channels in beta cell membrane) -> insulin release relies on increased ATP in the beta cell of the pancreas, which binds to the ATP dependent-K channel and closes it, depolarizing the membrane similar chemically to the thiazide diuretics but has no diuretic activity. It is bound extensively to serum albumin and to vascular tissue. The hypotensive effects of diazoxide are also greater when patients are pretreated with β blockers to prevent the reflex tachycardia and associated increase in cardiac output. Toxicity: most significant = excessive hypotension ; reflex sympathetic response can provoke angina, ECG evidence of ischemia, and cardiac failure in pts w/ ischemic heart disease Occasionally, hyperglycemia complicates diazoxide use, particularly in persons with renal insufficiency. In contrast to the structurally related thiazide diuretics, diazoxide causes renal salt and water retention. However, because the drug is used for short periods only, this is rarely a problem.

adrenergic neuron blocking agents- how do they work? what are the 2 major examples?

lower blood pressure by preventing normal physiologic release of norepinephrine from postganglionic sympathetic neurons Guanethidine & reserpine

Methyldopa - how is blood pressure reduction achieved? when is it primarily used? how does it enter the brain? Toxicity (other than sedation, there are 2 you should know)

lowers blood pressure chiefly by reducing peripheral vascular resistance, with a variable reduction in heart rate and cardiac output. now used primarily for hypertension during pregnancy One potential advantage of methyldopa is that it causes reduction in renal vascular resistance Methyldopa enters the brain via an aromatic amino acid transporter. Because the effect depends on accumulation and storage of a metabolite (α-methylnorepinephrine) in the vesicles of nerve endings, the action persists after the parent drug has disappeared from the circulation. most common toxic effect = sedation (particularly at onset of tx) -> may c/o mental lassitude and impaired mental concentration, nightmares, mental depression, vertigo, extrapyramidal signs (1) Lactation, associated with increased prolactin secretion (mediated by inhibition of dopaminergic mechanisms in the hypothalamus.) (2) postive Coombs test - makes cross-matching blood for transfusion difficult

Anatomic sites of blood pressure control (4) What mechanisms coordinate function at these 4 sites? How does regulation of BP differ between nl and hypertensive individuals?

maintained by moment-to-moment regulation of cardiac output and peripheral vascular resistance, exerted at three anatomic sites: arterioles, postcapillary venules (capacitance vessels), and heart. A fourth anatomic control site, the kidney, contributes to maintenance of blood pressure by regulating the volume of intravascular fluid. Baroreflexes, mediated by autonomic nerves, act in combination with humoral mechanisms, including the renin-angiotensin-aldosterone system, to coordinate function at these four control sites and to maintain normal blood pressure. Finally, local release of vasoactive substances from vascular endothelium may also be involved in the regulation of vascular resistance. Regulation of blood pressure in hypertensive patients differs from healthy patients in that the baroreceptors and the renal blood volume-pressure control systems appear to be "set" at a higher level of blood pressure

Toxicity of diuretics (6 major points)

most common adverse effect = potassium depletion hypokalemia may be hazardous in persons taking digitalis, those who have chronic arrhythmias, or those with acute myocardial infarction or left ventricular dysfunction. Potassium loss is coupled to reabsorption of sodium, and restriction of dietary sodium intake therefore minimizes potassium loss. Diuretics may also cause magnesium depletion, impair glucose tolerance, and increase serum lipid concentrations. Diuretics increase uric acid concentrations (increase its reabsorption at the proximal tubules) and may precipitate gout. The use of low doses minimizes these adverse metabolic effects without impairing the antihypertensive action. Potassium-sparing diuretics may produce hyperkalemia, particularly in patients with renal insufficiency and those taking ACE inhibitors or angiotensin receptor blockers; spironolactone (a steroid) is associated with gynecomastia.

nadolol, carteolol, betaxolol, bisoprolol as tx for HTN: how do the pharmacokinetics compare?:

nadolol and carteolol = nonselective, appreciably metabolized and excreted in urine (reduced dose with impaired renal function) betaxolol and bisoprolol = beta-1 selective, primarily metabolized by liver (long half-lives)

Guanethidine - why is it no longer used? why is it isolated to peripheral function? mechanism, toxicity, drug interactions:

no longer used in USA (may be used elsewhere) - in high enough doses, can produce profound sympathoplegia -> marked hypotension, diarrhea, impaired ejaculation too polar to enter CNS similar drugs: guanadrel, bethanidine, debrisoquin mechanism: inhibits release of norepinephrine from sympathetic nerve endings; tranported across sympathetic nerve membrane by NET, gets concentrated in transmitter vesicles, where it replaces norepinephrine and causes a gradual depletion of norepinephrine stores in the nerve ending Toxicity: symptomatic postural hypotension and hypotension following exercise ; delayed or retrograde ejaculation (into the bladder). diarrhea, which results from increased gastrointestinal motility due to parasympathetic predominance - Sympathomimetic agents, at doses available in over-the-counter cold preparations, can produce hypertension in patients taking guanethidine. - guanethidine can produce hypertensive crisis by releasing catecholamines in patients with pheochromocytoma. - When tricyclic antidepressants are administered to patients taking guanethidine, the drug's antihypertensive effect is attenuated, and severe hypertension may follow.

etiology of HTN:

only 10-15% of pts can establish a specific cause (secondary HTN) HTN w/ no specific cause = essential or primary HTN In most cases, elevated blood pressure is associated with an overall increase in resistance to flow of blood through arterioles, whereas cardiac output is usually normal. elevated blood pressure is usually caused by a combination of several (multifactorial) abnormalities. Epidemiologic evidence points to genetic factors, psychological stress, and environmental and dietary factors (increased salt and decreased potassium or calcium intake) as contributing to the development of hypertension.

Minoxidil: mechanism comparison of efficacy vs hydralazine Minoxidil must be used in combination with - toxicity: Topical minoxidil?

opening of potassium channels in smooth muscle membranes by minoxidil sulfate (active metabolite) increased K permeability stabilizes the membrane at its resting potential and makes contraction less likely dilates arterioles but not veins has greater antihypertensive effect than hydralazine and should replace it if max dose of the latter is not effective Even more than with hydralazine, the use of minoxidil is associated with reflex sympathetic stimulation and sodium and fluid retention. Minoxidil must be used in combination with a β blocker and a loop diuretic. Tachycardia, palpitations, angina, and edema reflex tachycardia and sympathetic stimulation) are observed when doses of co-administered β blockers and diuretics are inadequate. Headache, sweating, and hypertrichosis Topical minoxidil (as Rogaine) is used as a stimulant to hair growth for correction of baldness.

Fenoldopam- mechanism, major toxicities: should be avoided in pts with what condition?

peripheral arteriolar dilator used for hypertensive emergencies and postoperative hypertension agonist of dopamine D1 receptors- results in dilation of peripheral arteries and natriuresis. rapidly metabolized, primarily by conjugation major toxicities = reflex tachycardia, HA, flushing **also increases intraocular pressure - should be avoided in pts with glaucoma

Sodium nitroprusside - mechanism: pharmacokinetics and metabolism in the body: toxicity- how can serious toxicity be avoided via co-administration?

powerful parenterally administered vasodilator - used to treat hypertensive emergencies and severe heart fialure dilates both arterial and venous vessles, resulting in reduced PVR and venous return done via activation of guanylyl cyclase (release of NO or direct stimulation) - increased intracellular cGMP, which relaxes vascular smooth muscle In the absence of heart failure, blood pressure decreases, owing to decreased vascular resistance, whereas cardiac output does not change or decreases slightly. In patients with heart failure and low cardiac output, output often increases owing to afterload reduction. complex of iron, cyanide, and a nitroso moiety -> rapidly metabolized by uptake into RBCs w/ release of NO and cyanide ; cyanide metabolized by mitochondrial rhodenase in the presence of sulfur donor, to the less toxic thiocyanate -> distributed in extracellular fluid and slowly eliminated by the kidney rapidly lowers BP; effects disappear minutes after discont solution sensitive to light and must be made fresh before each administration and covered in foil Toxicity: other than excessive BP lowering: - serious toxicity due to accum of cyanide : metabolic acidosis, arrhythmias, death Administration of sodium thiosulfate as a sulfur donor facilitates metabolism of cyanide Thiocyanate toxicity is manifested as weakness, disorientation, psychosis, muscle spasms, and convulsions; hypothyroidism can occur due to thiocyanate inhibiting iodide uptake by thyroid methemoglobinemia also noted

Alpha-1 blockers for tx of HTN - mechanism? Why alpha-1 selectivity over nonselective drugs? Based on their mechanism, when would BP reduction be greater? Used primarily in pts with concurrent HTN and - What is the first-dose phenomenon? Other reported toxicities?

prazosin, terazosin, doxazosin antihypertensive effects by selectively blocking α1 receptors in arterioles and venules. These agents produce less reflex tachycardia when lowering blood pressure than do nonselective α antagonists such as phentolamine. Alpha1-receptor selectivity allows norepinephrine to exert unopposed negative feedback (mediated by presynaptic α2 receptors) on its own release Alpha blockers reduce arterial pressure by dilating both resistance and capacitance vessels. As expected, blood pressure is reduced more in the upright than in the supine position. (side effect = postural hypotension) used primarily in men with concurrent hypertension and benign prostatic hyperplasia. First dose phenomenon: Although long-term treatment with these α blockers causes relatively little postural hypotension, a precipitous drop in standing blood pressure develops in some patients shortly after the first dose is absorbed. For this reason, the first dose should be small and should be administered at bedtime. Although the mechanism of this first-dose phenomenon is not clear, it occurs more commonly in patients who are salt- and volume-depleted. Reported toxicities of the α1 blockers are relatively infrequent and mild. These include dizziness, palpitations, headache, and lassitude. Some patients develop a positive test for antinuclear factor in serum while on prazosin therapy, but this has not been associated with rheumatic symptoms.

Clonidine - how is blood pressure reduction achieved? when do the pressor effects of clonidine become of concern? How does clonidine enter the brain? How does dosing of clonidine differ from that of methyldopa? Toxicity of clonidine - concommitant therapy w/ what may block antihypertensive effects? Withdrawal sx?

reduction of cardiac output due to decreased heart rate and relaxation of capacitance vessels, as well as a reduction in peripheral vascular resistance. Reduction in arterial blood pressure by clonidine is accompanied by decreased renal vascular resistance and maintenance of renal blood flow. Pressor effects of clonidine are not observed after ingestion of therapeutic doses of clonidine, but severe hypertension can complicate a massive overdose. Clonidine is lipid-soluble and rapidly enters the brain from the circulation. Because of its relatively short half-life and the fact that its antihypertensive effect is directly related to blood concentration, oral clonidine must be given twice a day (or as a patch, below) to maintain smooth blood pressure control. However, as is not the case with methyldopa, the dose-response curve of clonidine is such that increasing doses are more effective (but also more toxic). Toxicity: - dry mouth and sedation common (centrally mediated and dose dependent) contraindicated in patients at risk for mental depression (concommitant tx w/ tricyclic antidepressants may block antihypertensive effects - believed to be due to α-adrenoceptor-blocking actions of the tricyclics.) Withdrawal from clonidine after protracted use particularly w/ high doses can result in life-threatening hypertensive crisis mediated by increased sympathetic nervous activity (nervousness, tachycardia, HA, sweating) -> if drug must be stopped, it should be done gradually while other antihypertensives are being substituted -> tx of hypertensive crisis: reinstitute clondine w/ alpha and beta adrenoceptor agents

Postural baroreflex:

responsible for rapid, moment-to-moment adjustments in BP (ex. transition from reclining to upright) Central sympathetic neurons arising from the vasomotor area of the medulla are tonically active. Carotid baroreceptors are stimulated by the stretch of the vessel walls brought about by the internal pressure (arterial blood pressure). Baroreceptor activation inhibits central sympathetic discharge. Reduction in stretch results in a reduction in baroreceptor activity In the case of transitioning to upright posture: -baroreceptors sense the reduction in arterial pressure that results from pooling of blood in the veins below the level of the heart as reduced wall stretch, and sympathetic discharge is disinhibited. The reflex increase in sympathetic outflow acts through nerve endings to increase peripheral vascular resistance (constriction of arterioles) and cardiac output (direct stimulation of the heart and constriction of capacitance vessels, which increases venous return to the heart), thereby restoring normal blood pressure