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Hypertension Treatment

Non Pharmacologic Measures

Weight loss should be initiated to achieve a normal BMI of 18.5 to 24.9 kg/m2 (1). A weight loss of 10kg is associated with a systolic blood pressure reduction of 5-20 mm Hg (1). A diet that is rich in fruits, vegetables, low fat dairy products with a reduced content of saturated and total fat should be initiated (1). This will result in an average reduction of 8-14 mm Hg of systolic blood pressure (1). Sodium intake should be reduced to less than 2.4 grams of sodium or 6 grams of sodium chloride per day (1). This corresponds with a 2-8 mm Hg reduction in systolic blood pressure (1). Regular aerobic physical activity performed for at least 30 minutes a day during most days of the week is associated with a 4-9 mm Hg reduction in systolic blood pressure (1). Alcohol consumption should be limited to less than or equal to 1 drink per day in women (1). This corresponds to a 2-4 mm Hg reduction in systolic blood pressure (1). Smoking cessation is recommended as it will reduce the risk of developing cardiovascular disease (1) . In circumstances where the average SBP/DBP is about 140-159/90-99 mm Hg, treatment is recommended if there is hypertensive target organ damage or if any additional risk factors are present, which was mentioned in the previous learning issue (4).

More than two-thirds of patients with hypertension will require two or more antihypertensive agents from different drug classes to be controlled (3). For example, in the ALLHAT, 60% of those whose blood pressure was controlled to less than 140/90 mm Hg needed two or more agents, whereas only 30 percent were controlled on one drug (2).

Diuretics

Diuretics, specifically a thiazide type diuretic is recommended as the first line agent in uncomplicated cases of hypertension (1,2,4). In patients that have or are strongly predisposed to having serious arrhythmias, an alternative first line agent should be used as diuretics can cause hypokalemia that can result in adverse cardiovascular outcomes (1,2,4). Thiazide diuretics work in a multifactorial way (2). There is an initial dieresis which reduces the plasma and stroke volume, which decreases the cardiac output and resultantly, the blood pressure (1,2). If used on a chronic basis, the extracellular fluid and the plasma volume will return to pretreatment values (1,2). But the peripheral vascular resistance decreases to values that are even lower than the baseline (1,2). Therefore, this reduction in the vascular resistance can be attributed to the long-term antihypertensive effects (1,2). Thiazide diuretics also mobilize sodium and water from the arteriolar walls (1,2). This increases and relaxes the diameter of the lumen, which results in less vascular resistance (1,2). The onset of action occurs approximately in 2 to 3 hours for most thiazides (1,7). These medications have a half life of approximately 8-12 hours; which allows once a daily dosing (7). Chlorthalidone is 1.5 to 2.0 times more potent than HCTZ, due to a longer half life (45 to 60 hours vs. 8 to 15 hours) and longer duration of effect (48 to 72 hours vs. 16 to 24 hours) (2). Side effects include hypokalemia, hypomagnesemia, hypercalcemia, dyslipidemia, hyperglycemia, however these effects are seen when high doses of thaizides are used (1,2,4). Limiting the dose of HCTZ or chlorthalidone to 12.5 to 25 mg/dose reduces the incidence of these side effects (1,2). Muscle fatigue or cramps may manifest and is usually attributed to the hypokalemia and hypomagnesemia effects of the thiazides (1,2). NSAIDs may reduce the hypotensive effectives of the thiazides (4). Furthermore, they are ineffective in patients with a ClCr <30 to 40 mL/min (4). While on thiazide diuretics, the SCr and K+ should be monitored (4). Most thiazides are eliminated in the urine as the unchanged parent drug (7). They are excreted by glomerular filtration and active secretion in the proximal tubule (7). Other classes of diuretics are also present (loop, potassium-sparing agents, and aldosterone antagonists) (1,2). Potassium sparing diuretics have a weak hypotensive effect (1,2).

The basis behind the recommendation of thiazide diuretics as a first line agent is due to the results from the ALLHAT study (3). A double blinded RCT of 42, 000 people, aged 55 or older with hypertension and at least one other coronary heart disease risk factor compared the effects of chlorthalidone versus lisinopril, amlodipine, or doxazosin on the primary outcomes of coronary heart disease mortality and nonfatal MI (3). Chlorthalidone was more effective at preventing combined cardiovascular events and strokes than doxazosin and was also better than preventing heart failure than amlodipine (3). Furthermore, there were lower rates of combined cardiovascular disease events, like stroke, heart failure when compared with lisinopril (3). To date, no drug class has proven more effective than lower dose thiazides when compared with placebo or no treatment (1,3).

Angiotensin Converting Enzyme Inhibitor

ACE inhibitors block ACE (bradykinase) and inhibits the conversion of angiotensin I to angiotensin II (1,2). Angiotensin II is a potent vasoconstrictor (1,2). In addition, it also stimulates aldosterone secretion that causes an increase in sodium and water reabsoprtion, with potassium losses (1,2). Since ACE is blocked, vasodilatation and a decreased amount of aldosterone will occur, which would lead to decreases in blood pressure. (1,2). ACEI are considered to be first line agents for non-black patients with uncomplicated hypertension and also for patients that have diabetes, ischemic heart diease, recent MI, heart failure or chronic kidney disease (1,3,4). They are first line treatment in patients that have past transient ischemic attacks in combination of HCTZ (1,2). ACEI are generally well tolerated, however, it can increase potassium concentrations in the serum, which may lead to hyperkalemia (4). This risk is especially pronounced in patients that have chronic kidney disease, or on potassium supplements, potassium-sparing diuretics or concomitant usage of NSAIDs and thus potassium level should be monitored (4). The GFR decreases in patients treated with ACEI or ARBS, and this is due to the inhibition of vasoconstriction on the efferent arteriole through the actions of blocking angiotensin II (1). Thus, the GFR should be monitored on a periodic basis (1). Angiodemia is a rare side effect (<1% of population), but is a serious potential complication (1). A persistent dry cough can also develop in up to 20% of the patients, and it is due to the inhibition of bradykinin breakdown (1,2) Dosing for ACEI should be low and should be lower if the patients have severe renal dysfunction (3) Dose titrations should be done slowly and should be adjusted no more rapidly than at 2 week intervals (1,2). Once the therapy has been initiated, the dose adjustments are done at approximately monthly intervals (1,2) The onset of action for ramipril is 1-2 hours and the duration of effect is 24 hours (5). Ramipril is metabolized through the hepatic route to the active form, ramiprilat (5). Excretion is 60% through the urine and 40% in the feces as the parent drug and metabolites (5).

The PROGRESS trial, illustrated that when a thiazide diuretic (indapamide) was added to an ACEI (perindopril), a 43% reduction in the incidence of recurrent stroke in patients with a history of ischemic stroke (3,6,9). This reduction was even seen in patients that had blood pressure values less than 140/90 mm Hg (3,6,9). Recurrent strokes were not seen when the patients were only a monotherapy of ACEI (3,6,9). Only the addition of a thiazide type diuretic to the ACEI led to this reduction in recurrent strokes (3,6,9). This combination also reduced the average systolic blood pressure by 12 mm Hg and the average diastolic blood pressure by 5 mm Hg (6,9). The HOPE trial illustrated that ramipril significantly reduces the occurrence of MI, stroke, CV death and all cause death compared to placebo in high risk patients, including hypertensive patients (6).

Angiotensin Receptor Blockers

ARBs work by directly blocking the angiotensin II receptor subtype 1 receptor that is mainly responsible for the known effects of angiotensin II, which is vasoconstriction, aldosterone release, sympathetic activation, antidiuretic hormone release, and constriction of the efferent arterioles of the glomerulus (1,2,3). Since, ARBs are specific to the angiotensin II receptor subtype 1, and do not affect the subtype 2 receptor, the beneficial effects of angiotensin II receptor subtype 2 stimulation, which include vasodilation, tissue repair, and cell growth are not blocked when ARBs are used (1,2). ARBs may cause renal insufficiency, hyperkalemia, and orthostatic hypotension (1,2). Patients that take potassium supplements or potassium sparing diuretics are especially prone to hyperkalemia and should have their potassium levels monitored (4). The maximum hypotensive effect is achieved in about 2-3 weeks after starting therapy (1). Eprosartan is eliminated by biliary and renal excretion, mostly as the unchanged parent drug (5). ARBs are generally first line agents for hypertension (4). There is data showing long term reductions in the progression to target organ damage in patients that have hypertension (1). The MOSES study illustrated that eprosartan reduced the occurrence of recurrent stroke more than nitrendipine in patients with a past history of cerebrovascular disease (6).

Beta Blockers

β-blockers that have negative chronotropic and inotropic effects reduce cardiac output which in turn lowers the blood pressure (1,2) Furthermore, they may also inhibit β-adrenoceptors at the juxtaglomerular cells to prevent the release of renin (1,2). Cardioselective β-blockers, such as atenolol, and metoprolol have greater clinically significant advantages over nonselective β-blockers, such as (propranolol, nadolol) as they are safer in patients with hypertension (1,2) Adverse effects include fatique, bradycardia, decreased exercise capacity, and headaches (1,2,4). β-blockers can interact with digoxin or nondihydropyridine CCB to cause bradycardia (1,2). Furthermore cardiodepressant effects are noted with nondihydropyridine CCBs and amiodarone (1,2) β-Blockers are also contraindicated in patients with asthma and severe peripheral artery disease (4). They are contraindicated in patients with a 2nd or 3rd degree heart block in the absence of a pacemaker (4). Abrupt withdrawal may precipitate ischemia (4). Furthermore, β-blockers should not be used as initial therapy in patients >60 years as a recent 2005 meta analysis noted that β-blockers had a 16% relative risk of stroke compared to other drugs (8). The onset of action for atenolol is 2-4 hours (5). It is metabolized limitedly through the hepatic route and 40% of the drug is excreted as the unchanged drug in urine (5).

Calcium Channel Blockers

Calcium channel blockers work by inhibiting the calcium influx through the membrane bound voltage dependent calcium channels, and this result in decreased intracellular calcium cells, and a prevention of cardiac and smooth muscle contraction (1,2). There are two subclasses of CCBs which are pharmacologically different from each other; however, the antihypertensive effects are similar (1). Nondihydropyridines decreases the heart rate and also slow the atrioventrical nodal conduction, whereas dihydropyridines have potent peripheral vasodilating effects (1). Side effects of CCB, especially the dihydropyridine CCBs include headache, dizziness, peripheral edema, and flushing (1,4). Nondihydropyridine CCBs can cause headache, bradycardia, new onset or worsening of heart failure (1,4). Short acting immediate release formulations of DHP CCBs have shown to increase cardiovascular events in RCTs and should be avoided (1,2,3). CCBs are considered to be first line agents (4). New data shows that they are as likely to be effective as lowering CV events as other agents (3). DHP CCBs are a substrate for CYP3A4 and inhibitors of this medication include azole antifungals, protease inhibitors, macrolides and quinidine (4). DHP CCBs are hepatically metabolized (>90%) to inactive metabolites and the duration of the antihypertensive effect is 24 hours (1,2). This subclass is also eliminated via the urine (5). NDHP CCBs inhibit the metabolism of carbamazepine, cyclosporine, lovastatin, and simivastatin (1,2). Diltiazem (NDHP CCBs) has been shown to be as effective as a diuretic and a beta-blocker in reducing CV events (fatal/non-fatal stroke, MI and CV death) in the NORDIL study (6). NDHP CCBs are eliminated in the urine and have an extensive first pass effect through hepatic metabolism (1,2).

Alpha Blockers

Alpha blockers are used as second line agents on top of most other agents in patients whose hypertension is not controlled (1,2). Dizziness or palpitations following the first dose and orthostatic hypotension after long term use limits its use in therapy (1,2). The benefit of this class of medications in long term therapy is unknown as there are no long term randomized control trials that examine the renal or cardiovascular outcomes after using this drug (1,2). The ALLHAT trial had an arm that compared an α-blocker, doxazosin, with a β-blocker, a calcium channel blocker, and an ACE inhibitor versus a diuretic (1,2,5). However, the study had to be stopped prematurely since patients that received the alpha blocker had an increase of cardiovascular events (1,2,5). Average reduction in systolic pressure is 8 mm Hg and 5 mm Hg for diastolic pressure in ten trials involving 1175 subjects (1). Doxazosin lasts for more than 24 hours (5). It is extensively metabolized through the hepatic route, mainly via CYP3A4 to active metabolites (5). Excretion is through the feces and the urine (5). Beta-blockers may enhance the orthostatic hypotensive effect of Alpha blockers (5).

References

  1. Chisholm-Burns MA, Wells BG, Schwinghammer TL, Malone PM, Kolesar JM, Rotschafer JC, Dipiro JT. Pharmacotherapy: Principles and Practice. McGraw-Hill: 2008. p. 9-31.
  2. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2007. p. 139-68.
  3. Norman GAV, Jones R, Townsend R, Cohen D. Hypertension. MD Consult [online]. Maryland Heights MO: Elsevier Inc. 2011 [cited 2011 Nov 6]. Available from: www.mdconsult.com
  4. Repchinsky C, editor-in-chief. Therapeutic Choices. 6th ed. Canadian Pharmacists Association; 2011. p. 450-3.
  5. Ramipril, atenolol, doxazosin, diltiazem. In: Drug Monographs [online]. McGraw-Hill’s Access Medicine; No date [cited 2011 Nov 6]. Available from: http://www.accessmedicine.com/
  6. Jensen B, Regier LD, editors. RxFiles – Drug Comparison Charts, 8th ed. Saskatoon: Saskatoon Health Region; 2010. p 6-7.
  7. McEvoy GK. Thiazide diuretics. In: AHFS Drug Information. [Online]. 2009. Available from: Medicines Complete. London (UK): Pharmaceutical Press; 2009. [cited 2011 Nov 6].
  8. Lindholm LH, Carlberg B, Samuelsson O. Should β blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005; 366(9496): 1545-53. DOI: 10.1016/S0140-6736(05)67573-3
  9. Van Gijn J. The PROGRESS Trial: Preventing Strokes by Lowering Blood Pressure in Patients With Cerebral Ischemia: Emerging Therapies: Critique of an Important Advance. Stroke 2002;33:319-20.

Disclaimer

This information is presented for informational purposes only and is not meant to be a substitute for advice provided by qualified health care professionals. You should contact your qualified health care provider if you have or suspect any health problems. This article is not intended to provide medical advice for its readers


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