First- line antihypertensives
Mechanisms of action, adverse effects and potential interactions
Hypertension is estimated to affect 23% of the Canadian population, or approximately six million adults. Prevalence increases with age: more than 70% of adults over the age of 80 are affected by this condition (Robitaille 2011).
Elevated blood pressure is a well-established risk factor for cardiovascular events including myocardial infarction and stroke (Leone 2011). Chronic kidney disease and other conditions are complicated and exacerbated by hypertension (Koizumi 2011). In light of the risks associated with this presentation, blood pressure reduction is an important therapeutic goal.
Although lifestyle changes including weight reduction, exercise prescriptions and diet modifications are primary recommendations in sustainable hypertension management, pharmacological therapies are commonly used. Current recommendations from the Canadian Hypertension Education Program (CHEP) indicate that first-line drug therapy should consist of one of the following agents:
• A thiazide diuretic;
• A beta-blocker;
• An angiotensin-converting enzyme inhibitor (ACE inhibitors);
• A long-acting calcium channel blocker (CCB); or
• An angiotensin receptor blocker (ARB). Should monotherapy be ineffective, a combination of select agents is encouraged (Rabi 2011).
This review will examine these five classes of drugs, describing their mechanism of action, adverse effects and potential interactions with drugs, nutrients and endogenous substances.
Mechanisms of blood pressure regulation
Adequate circulatory pressure ensures appropriate perfusion of all tissues of the body, supporting the delivery of oxygen, nutrients and other essential factors to all cells. The crucial task of blood pressure regulation relies upon the interplay of numerous physiologic systems.
The renin-angiotensin-aldosterone system (RAAS) is integral to the dynamics of blood pressure regulation (Crowley 2007) and has a powerful influence upon vascular tone and fluid volume. This system is the target of ACE inhibitors and ARBs.
Renin, a proteolytic enzyme, is central to the RAAS. Once secreted by the juxtaglomerular cells of the kidneys, renin cleaves inactive angiotensinogen circulating in the blood. Angiotensin I is formed and converted in turn to angiotensin II by angiotensin-converting enzyme (ACE) (Raebel 2011). Angiotensin II goes on to stimulate angiotensin 1 receptors (AT1) in the heart, blood vessels, kidney, adrenals and brain, causing vasoconstriction, vasopressin and aldosterone release, sodium retention and increased sympathetic activity (Burnier 2001, Raebel 2011). Systemic blood volume and pressure increase as a result.
Interactions between ACE and bradykinin further increase circulatory pressure. Bradykinin promotes vasodilation through nitric oxide release while encouraging salt loss through the urine (Piepho 2000); ACE inactivates bradykinin through a cleaving process.
Calcium dynamics are important to the maintenance of vascular tone (Richard 2005). Influx of calcium across cell membranes causes contraction of smooth muscle cells lining the circulatory system, resulting in vasoconstriction and an increase in blood pressure. This mechanism is the therapeutic target of calcium channel blockers (CCBs).
The sympathetic nervous system can induce changes in vascular tone, renin levels and cardiac function. Adrenergic receptors in numerous organs and tissues respond to catecholamine release causing:
• increased heart rate and output (through beta-1 receptors);
• vasoconstriction and vasodilation (through alpha-2 and beta-2 receptors); and
• increased renin production (through beta-1 receptors).
Beta-type adrenoreceptor blocking drugs (beta-blockers) act upon these receptors with varying degrees of selectivity (Gorre 2010).
Finally, appropriate blood pressure levels require adequate intravascular fluid. Complex neurohormonal mechanisms involving the kidneys, the thirst response, aldosterone and anti-diuretic hormone (ADH) ensure that fluid is conserved and excreted from the body as needed (Thornton 2010).Thiazide diuretics influence this system, promoting fluid loss and decreasing blood pressure.
THIAZIDE DIURETICS
Thiazide diurectics have been used in the management of hypertension for over 50 years (Sarafidis 2010). Still considered a first-line agent, thiazide diuretics appear to be more beneficial than other anti-hypertensives in their ability to reduce cardiovascular morbidity and mortality (Wright 2009). Thiazide diuretics have also been shown to be more effective than ACE inhibitors or ARBs in patients of African descent (Taylor 2005).
Mechanism of action
Thiazide diuretics act at the distal convoluted tubule of the nephron, inhibiting the activity of the NaCl co-transport pathway (Sarafidis 2010). The action of these drugs prevents the resorption of sodium and chloride at this site and promotes fluid loss through the urine.
Paradoxically, fluid levels return to pre-treatment levels within four to six weeks of treatment initiation, yet pressure decrease is maintained. This hypotensive effect may be explained through the apparent ability of thiazide diuretics to reduce peripheral vascular resistance and blood pressure, but the mechanism is not understood at present (Duarte 2010).
Adverse effects
Higher levels of sodium in the collecting duct of the nephron result in increased potassium loss, creating the potential for both hyponatremia (Egom 2011) and hypokalemia. Potassium loss can increase the risk of sudden cardiac death although the use of lower-dose regimens and concurrent ACE inhibitors may attenuate this risk (Krämer 2000). Hypokalemia is cited as a possible cause of new-onset diabetes associated with thiazide diuretic use (Sica 2011). Magnesium loss (Sarafidis 2010) and uric acid retention (Sica 2011) are also associated with thiazide diuretic use.
Erectile dysfunction has been reported in men using thiazide diuretics (Francis 2007). Dyslipidemia has also been attributed to thiazide use, but newer research suggests inconsistent effects upon lipid levels in the absence of increased cardiovascular risk (Deano 2012).
Potential interactions
Care should be taken with any drugs that decrease potassium, magnesium or sodium levels as an additive effect may result. The hypotensive effect of thiazide diuretics may be decreased with NSAID use (Sica 2011). Digoxin intoxication has been associated with concomitant diuretic use (Wang 2010).
Plasma homocysteine levels may be increased with thiazide diuretic use (Westphal 2003). Additional monitoring of homocysteine levels may be necessary in these patients.
BETA-BLOCKERS
Beta-blockers have been used since the mid-1960’s in the management of cardiovascular conditions (Chrysant 2008). This diverse class includes both lipophilic and hydrophilic drugs, varying in their receptor selectivity and duration of effect. Beta-blockers continue to be considered first line agents in the management of hypertension (Rabi 2011) despite recent criticisms of their ability to prevent stroke and other negative outcomes in comparison to other anti-hypertensives (Wiysonge 2007).
Mechanism of action
Beta-blockers exert their influence by competing with catecholamines for absorption by beta-1 adrenergic receptors. This binding blocks the effect of endogenous neurotransmitters, decreasing the effects of the sympathetic nervous system causing reduced blood pressure, heart rate and cardiac contractility. Non-selective beta-blockers such as propanolol may also act upon beta-2 receptors in the lungs, causing undesirable pulmonary effects in some individuals (van der Woude 2005). Newer agents (carvedilol and nebivolol) promote additional vasodilation through nitric oxide production (Chrysant 2008).
Adverse effects
Depression associated with beta-blocker prescription has been reported in the literature (Patten 1990) although much current research does not support this association (Ko 2002, Verbeek 2011). Others suggest that while depressive symptoms may occur with beta-blockers use, the effect is limited to lipophilic agents (propanolol, alprenolol) that can cross the blood-brain barrier (Luijendijk 2011).
Sexual dysfunction and fatigue have been associated with beta-blocker use (Ko 2002) but may again be related to the specific agents used (Brixius 2007). In addition, some beta-blockers may increase the risk of developing new-onset diabetes (Gorre 2010). It is unclear whether newer vasodilating agents such as carvedilol, nebivolol and labetolol share these properties with older agents (Ram 2010).
Non-selective beta-blockers have been contraindicated in patients with lung disorders as inhibition of the beta-2 adrenoreceptors in the lungs may cause bronchospasms in these patients (Kendall 1997). Newer drugs that are selective for beta-1 receptors have not been found to cause the same issues and appear to be safe for use in patients with pulmonary concerns (Salpeter 2005).
Like ACE inhibitors and ARBs discussed below, beta-blockers increase the risk of hyperkalemia as a result of decreased renin production (Takaichi 2007).
Potential interactions
Care should be taken with concomitant use of any other drugs with hypotensive or negative inotropic or chronotropic effects. Interactions between beta-blockers and NSAIDs such as ibuprofen have also been reported in the literature (Salort- Llorca 2008) resulting in decreased effectiveness of this antihypertensive medication.
Melatonin production appears to be impaired by some beta-blockers (Stoschitzky 1999) with the notable exception of carvedilol. Melatonin supplementation may be indicated in patients treated with drugs from this class (Fares 2011).
ACE INHIBITORS
ACE inhibitors form a diverse group of drugs that inhibit the RAAS through their action upon angiotensin-converting enzyme (ACE).
Mechanism of action
ACE inhibitors bind to ACE through the formation of zinc ligands (Piepho 2000). The production of angiotensin II is thereby impaired, preventing AT1-mediated increases in vascular tone, aldosterone production and bradykinin degradation (Hayduk 1999). The RAAS is essentially inactivated, preventing further increases in blood pressure.
Adverse effects
The most common adverse effect associated with ACE inhibitor use is a dry cough (Semple 1995) that while not serious, can prompt treatment discontinuation. Cough is believed to be associated with an accumulation of bradykinin secondary to ACE inhibition (Mas 2011).
Patients using ACE inhibitors are also at risk of hyperkalemia (Raebel 2011), resulting from the ACE-mediated decrease in aldosterone production (Piepho 2000). This adverse effect may be more pronounced with concomitant renal or cardiac failure (Izzo 2011). ACE inhibitors are not recommended in patients with renal stenosis (Parish 1992). Other reported adverse effects include angioedema (Izzo 2011), rash, dizziness, gastrointestinal (GI) effects, hypotension and altered taste (Parish 1992).
The safety of ACE inhibitors has not been clearly established in pregnancy. Although significant adverse effects to the fetus have not been seen in some trials (Diav-Citrin 2011), this class of drugs is generally regarded as contraindicated during pregnancy (Cooper 2006, Izzo 2011).
Potential interactions
Many drug-drug interactions are possible with ACE inhibitor use (Hines 2011). Lithium toxicity is possible with concurrent ACE inhibitor use (Piepho 2000) and NSAIDs can decrease the anticipated hypotensive effect of this intervention (Piepho 2000, Salort-Llorca 2008).
A small crossover study found that N-acetyl cysteine (NAC) may potentiate the hypotensive effect of captopril and enalapril (Barrios 2002). This may be a desirable effect in some patients. Endogenous zinc levels may be depleted by ACE inhibitor use (Golik 1998)
CALCIUM-CHANNEL BLOCKERS (CCBs)
CCBs have been in use for half a century (Nayler 1986) and have evolved through several generations of drugs from short-acting drugs (verapamil), through longer-acting drugs (nisoldipine), to newer, slower-release drugs with great affinity for their designated receptors (manidipine, lercanidipine) (Richard 2005).
Mechanism of action
Contraction of muscular tissue lining the circulatory system is mediated in part by intracellular calcium levels. CCB-type drugs bind to the calcium channels that govern the flow of calcium across cellular membranes and inactivate them, preventing the influx of calcium and subsequent contraction of vascular tissue. (Richard 2005). Some CCBs may also decrease heart rate and contractility, especially first-generation CCBs (Noll 1998). Blood pressure is decreased as a result.
Numerous sub-types of calcium channels have been identified. L-type channels are dominant through the vascular system and are the target of dihydropyridine CCBs such as amlodipine and nicardipine. Newer agents including manidipine, benzindamine and nilvadipine may act upon T-type channels found in the kidneys, conferring renal protection in comparison to older drugs. Other channels (P/Q type and others) are being investigated as potential therapeutic targets (Hansen 2011).
Adverse effects Peripheral dependent edema is a significant side effect, especially with the use of first- and second-generation CCBs (Burnier 2009). Earlier concerns with increased risk of MI seem to have been associated with large doses of shorter-acting agents rather than drugs in current use (Kaplan 1996). Headaches and flushing are common effects (Makarounas-Kirchmann 2009) in addition to rash, nausea and drowsiness. High-dose verapamil may cause constipation (Elliott 2011).
Calcium channel blockers are used in pregnancy, but a recent retrospective study found an increased risk of infant seizures with pre-term CCB exposure (Davis 2011).
Potential interactions
Plasma levels of cyclosporine and digoxin may be increased by diltiazem and verapamil (Elliott 2011). Many other potential drug-drug interactions exist between CCBs and inhibitors and inducers of CYP3A4. For this reason, CCBs should not be taken with grapefruit juice (Sica 2006a). A recent trial (Koziróg 2011) demonstrated reduced efficacy of nifedipine when used in conjunction with melatonin. Competition for common binding sites may explain this interaction. This drug may also decrease copper levels and increase zinc levels (Misiewicz 1998) but the magnitude and clinical significance of this effect has not been established.
ANGIOTENSIN RECEPTOR BLOCKERS (ARBs)
ARBs are comparatively new additions to the spectrum of hypertensive drugs, with losartan, the first drug in this class, being introduced in 1995 (Sica 2006). Their efficacy appears to be comparable to that of ACE inhibitors (Matchar 2008).
Mechanism of action
Like ACE inhibitors, ARBs affect the RAAS directly, preventing angiotensin II from exerting pressure-increasing effects upon the circulatory system. ARBs are angiotensin II antagonists, binding competitively to type 1 angiotensin receptors and decreasing blood pressure as a result. Some decreases in plasma aldosterone levels may also be anticipated through this effect (Sica 2006).
Adverse effects
In comparison to other antihypertensive agents, ARBs appear to have fewer associated adverse effects (Matchar 2008) and are generally well-tolerated. Notably, ARBs are not associated with a dry cough, unlike ACE inhibitors (Fogari 2011). GI disturbance, fatigue, dizziness, headache and hyperkalemia may present with ARB use (Fogari 2011, Raebel 2011).
Some concerns have been raised recently regarding associations between ARBs and cancer, based upon both meta-analyses (Bangalore 2011, Sipahi 2010) and population studies (Chang 2011). Others have not found evidence of any risk with ARB use (Yoon 2011). Current recommendations advise continued use of ARBs pending further investigation of this link, citing established benefits to cardiovascular health and a lack of conclusive evidence of risk (Rabi 2011, Volpe 2011).
Populations that should not use ARBs include individuals with kidney disease (Sipahi 2010). Acute renal failure may result from use by individuals with renal stenosis (Burnier 2001). ARBs are also not recommended for use in pregnancy (Alwan 2005) although small studies have not shown detriment from early exposure (Diav-Citrin 2011).
Potential interactions
Increased digoxin levels (Elliott 2006) have been reported with ARB use. Other drug-drug interactions are possible. ARBs including valsartan and eprosartan should not be taken with food as this may decrease absorption by up to 40% (Burnier 2001). Like other hypertensive agents, ARBs appear to interact with zinc, promoting excretion and potential deficiency (Koren- Michowitz 2005).
CONCLUSION
Current guidelines encourage the use of pharmacological therapy in the management of hypertension using drugs from the five classes described above. A thorough understanding of mechanisms, interactions and potential adverse effects will encourage safe and effective clinical use of these agents.
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