Which antihypertensive medications are most likely to cause tachycardia?

• Antihypertensive drugs are frequently used by patients and may influence conduct of anaesthesia.

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  • Pharmacological management of hypertension
  • Drugs which target the RAS
  • Direct renin inhibitors
  • Should drugs which target the RAS be used perioperatively?
  • Adrenoceptor antagonists
  • β-Blockers
  • α-Blockers
  • Calcium channel blockers
  • Other antihypertensives
  • Vasodilators
  • Centrally acting agents
  • Ganglion blockers
  • Declaration of interest
  • Which antihypertensive drug causes tachycardia?
  • Do ACE inhibitors cause tachycardia?
  • Do calcium channel blockers cause tachycardia?
  • Does amlodipine cause reflex tachycardia?
  • Does nifedipine cause tachycardia?
  • Can hydralazine cause tachycardia?

• Relatively few drug classes are used to treat hypertension, the newest of which are direct renin inhibitors.

• The renin–angiotensin system is targeted at different points by many of the commonly used antihypertensive drugs.

• Antihypertensive drugs have diverse indications, both cardiac and non-cardiac.

• Guidance on antihypertensive agents is provided by the National Institute for Health and Care Excellence.

Antihypertensive drugs comprise several classes of compound with the therapeutic intention of preventing, controlling, or treating hypertension. The classes of antihypertensive drug differ both structurally and functionally. They are important in anaesthetic practice because they are commonly prescribed to the general population, with the overall prevalence of hypertension being 31% in the UK [defined by the National Institute for Health and Care Excellence (NICE) as a measurement of 140/90 mm Hg or higher in clinic, with subsequent ambulatory or home measurement of 135/85 mm Hg or higher].1 Antihypertensive drugs are used frequently in other unrelated conditions, for example, β-blockers in thyrotoxicosis and anxiety, or angiotensin-converting enzyme inhibitors (ACEIs) in heart failure. Hence both the drug and its indication are relevant to the conduct of anaesthesia.

This article focuses on the applied pharmacology of agents commonly encountered in UK clinical practice, their therapeutic and side-effects, drug interactions, and implications for anaesthesia and surgery. The causes of hypertension are summarized in Table 1.

Table 1

Summary of causes of hypertension

Table 1

Summary of causes of hypertension

Pharmacological management of hypertension

The majority of hypertensive patients have primary (or essential) hypertension, that is, hypertension in which secondary causes are not present. Management aims to control arterial pressure, prevent end-organ damage (cerebrovascular, cardiovascular, and renal), and reduce the risk of premature death.1

Arterial pressure may be lowered by reducing cardiac output, systemic vascular resistance (SVR), or both (Fig. 1). Drugs manipulating SVR may also bring about clinical improvement through modification of vascular compliance and reactivity. For example, the β-blockers carvedilol and atenolol reduce arterial pressure similarly at rest, but carvedilol is associated with improved vascular compliance.

Fig 1

Overview of the mechanisms of action of common classes of antihypertensive drugs. There may be considerable overlap between some of the groups, for instance, thiazide and loop diuretics cause vasodilatation and diuresis.

Drugs may be classified by mechanism or site of action.2 Within each class, there are multiple drugs with structural and pharmacological variations resulting in differing therapeutic and side-effects (Table 2). Many agents do not have a ‘clean’ mechanism of action, but act on multiple pathways.

Table 2

Classes and subclasses of antihypertensive medications with common examples

Table 2

Classes and subclasses of antihypertensive medications with common examples

Antihypertensives may be divided into two broad groups,3 the first group being those which directly or indirectly block the renin–angiotensin system (RAS), for example, ACEIs, angiotensin receptor antagonists (ARAs), direct renin inhibitors (DRIs), and to a lesser extent β-blockers. While these drugs have multiple mechanisms of action, their predominant effect is to cause vasodilatation. The second group of drugs works by increasing water and sodium excretion, thereby reducing intravascular volume, or by causing vasodilatation through non-RAS pathways, for example, diuretics and calcium channel blockers (CCBs). The actions of this second group increase RAS activity through negative feedback, a result of which is that they can potentiate the activity of drugs which target and inhibit the RAS.

The appropriate choice of antihypertensive drug depends on which groups of drugs are most likely to be effective both in controlling arterial pressure and in preventing complications such as end-organ damage. Current NICE guidance recommends that patients under the age of 55 be initiated on drugs which target the RAS as first-line therapy. Patients aged over 55 and black people of African or Caribbean family origin are initially treated with drugs which act through non-RAS mechanisms, as these latter patient groups typically have low-renin hypertension. Additionally, there may be compelling individual indications or contraindications for the use of a particular drug class.1

Drugs which target the RAS

Three drug classes directly target points of the RAS pathway. They act to reduce production of the peptide hormone angiotensin II, or reduce its receptor binding (Fig. 2). Angiotensin II has high affinity for AT1 G-protein-coupled receptors, activation of which causes increased arteriolar tone and SVR. It also causes sympathetic nervous system activation, increased pituitary secretion of antidiuretic and adrenocortocotrophic hormones, and increased adrenocortical secretion of aldosterone.4 By antagonizing the RAS pathway, SVR and arterial pressure are reduced. This effect is potentiated by a reduction in aldosterone secretion with resultant reduction in renal sodium and water retention. Negative feedback results in increased renin release by the juxtaglomerular apparatus.

Fig 2

Sites of action of drugs affecting the renin–angiotensin system. ACEI, angiotensin-converting enzyme inhibitor. ARB, angiotensin receptor blocker.

ACEI drugs

The discovery that the venom of the Brazilian pit viper, which causes a massive decrease in arterial pressure, works by inhibition of angiotensin-converting enzyme (ACE) led to the development of synthetic, orally administered ACEIs.

ACEIs are first-line treatment in patients under 55 yr old with primary hypertension.1 They are also indicated in heart failure, post-myocardial infarction, diabetic nephropathy, and chronic kidney disease (although not acute kidney injury). The renal and cardiac protective effects of ACEIs are greater than those expected by arterial pressure control alone.5

ACE is a metallopeptidase enzyme which occurs mainly within the pulmonary vasculature. The inhibition of ACE reduces the cleavage of the peptide hormone angiotensin I to angiotensin II and reduces metabolism of the peptide bradykinin to inactive substances. The reduction in angiotensin II is responsible for most of the therapeutic effects. The accumulation of bradykinin has some therapeutic advantage through vasodilatation, but is also responsible for a dry cough in susceptible individuals. ACEIs can also precipitate renal dysfunction by decreasing renal efferent arteriolar tone, thereby decreasing effective renal perfusion pressure, a particular risk in renal artery stenosis. Other side-effects include hyperkalaemia due to reduced aldosterone secretion, agranulocytosis, skin rashes, and taste disturbance. A rare idiosyncratic reaction to ACEIs can cause angiooedema with potential upper airway obstruction; this can occur several years after initiation of ACEI therapy. ACEIs are contraindicated in pregnancy as they are associated with birth defects.

ACEIs are administered orally with the exception of i.v. enalaprilat (the active form of enalapril). Enalapril, ramipril, and perindopril are prodrugs requiring hepatic esterification for activation. Captopril is an active drug converted to active metabolites by the liver. Lisinopril is an active drug, excreted unchanged. Most ACEIs are excreted predominantly by the kidney.

ACEIs may interact with drugs used perioperatively. For example, non-steroidal anti-inflammatory drugs can precipitate renal dysfunction in combination with ACEIs. They can also reduce the efficacy of ACEIs by decreasing prostaglandin synthesis. Interactions with diuretics may cause hypovolaemia and hyponatraemia, while concurrent use of potassium supplements or potassium-sparing diuretics may result in hyperkalaemia. Drugs which are renally excreted (e.g. digoxin and lithium) may accumulate in patients taking ACEIs.

There is increased risk of hypotension on induction of anaesthesia in patients who have recently taken an ACEI, which may necessitate the use of vasopressor drugs in order to restore arterial pressure.6,7 To date, there is no high level evidence of worse clinical outcomes in patients who have taken ACEIs on the day of surgery.

ARA drugs

ARAs are commonly used in patients who are intolerant of ACEIs as they are less likely to cause a dry cough. The therapeutic and side-effects are broadly similar to those of ACEIs, with evidence of reduced risk of new onset diabetes, stroke, progression of cardiac failure, and all-cause mortality in patients with chronic kidney disease.

ARAs are orally administered drugs which target AT1 G-protein-coupled receptors to antagonize the effect of the peptide hormone angiotensin II. Some drugs (candesartan and telmisartan) bind irreversibly, while others (losartan and valsartan) are competitive antagonists.

Direct targeting of angiotensin II receptors has theoretical advantages over ACE inhibition. Angiotensin II may be produced through non-ACE pathways, for example, by the enzyme chymase in kidney tissue, which is not affected by ACEIs. ARAs do not inhibit bradykinin metabolism, and therefore, the incidence of cough is much less than with ACEIs. The risk of angiooedema is greatly reduced with ARAs compared with ACEIs.

As with ACEIs, patients taking ARAs are at increased risk of episodes of hypotension after induction of anaesthesia, particularly when taken in combination with diuretics.7

Direct renin inhibitors

Aliskiren, a piperidine derivative, is the only available drug in this class and is used by specialists in patients who are unresponsive to, or intolerant of, other antihypertensives. Aliskiren directly inhibits the enzyme renin, which is secreted by granular cells of the juxtaglomerular apparatus. Renin inhibition reduces the conversion of the hepatically secreted polypeptide angiotensinogen to angiotensin I. Its effect on the RAS is therefore ‘upstream’ of ACEIs and ARAs and it does not cause bradykinin accumulation. DRIs have the same potential to cause renal dysfunction and electrolyte disturbances as ACEIs and ARAs. Diarrhoea is a specific side-effect to higher doses of DRIs.

Aliskiren is orally administered, although it is poorly absorbed and its bioavailability is low (2.7%); therefore, therapeutic plasma concentration is only achieved by repeat dosing. It is minimally metabolized and its main route of elimination is biliary. Therefore, it has a long elimination half-life (24–40 h).3

Aliskiren may have a larger role in the management of hypertension in future, possibly in combination with other drugs. Evidence relating to the implications of aliskiren therapy on anaesthetic conduct is limited, although there are case reports of patients having prolonged and refractory hypotension after induction of general anaesthesia.

Should drugs which target the RAS be used perioperatively?

There are currently no universal guidelines on whether RAS-blocking drugs should be withheld before surgery. However, in many departments, local guidelines recommend that ACEIs and ARAs be withheld on the day of surgery in order to reduce the risk of hypotension and organ hypoperfusion under anaesthesia. This approach should be balanced against the potential beneficial effects of continuing these drugs perioperatively. Some authors recommend that patients with heart failure or resistant hypertension continue to take ACEIs perioperatively. The potential benefits of this approach may outweigh the risks, provided care is taken to maintain euvolaemia and episodes of hypotension are managed with volume expansion and vasopressors. Other described benefits of continuing RAS antagonists in the perioperative period include renal protection, reduced rates of perioperative atrial fibrillation, and neuroprotection in cerebrovascular surgery.8

Adrenoceptor antagonists

β-Blockers

β-Blockers are not used as first-line antihypertensives unless there are other indications, for example, after myocardial infarction, or in tachyarrhythmias such as atrial fibrillation. Their diverse indications include stable heart failure, thyrotoxicosis, oesophageal varices, anxiety, and glaucoma.

β-Blockers antagonize catecholamines at β-adrenoceptors. These Gs type G-protein-coupled receptors are classified as β1, present mainly within the heart and kidneys; and β2, present throughout the body in lungs, blood vessels, and muscle. The reduction in arterial pressure achieved by β-blockers is attributable to their effects upon multiple pathways. Block of β1 receptors in the sinoatrial node reduces heart rate and block of myocardial receptors reduces contractility (reduced chronotropy and inotropy, respectively). They also reduce sympathetic nervous system activity, while block of receptors in the juxtaglomerular apparatus reduces renin secretion.

β-Blockers are categorized according to cardioselectivity. Metoprolol, esmolol, and atenolol have greater affinity for β1 receptors than β2 at therapeutic doses (selectivity is reduced at higher doses). This contrasts with non-cardioselective drugs such as propranolol and sotalol. Most β-blockers are pure antagonists; however, some drugs are partial antagonists at β receptors and exhibit some agonist/sympathetomimetic activity (pindolol, timolol). The clinical relevance of this is uncertain. Some β-blockers (propranolol, metoprolol) block sodium channels and have membrane stabilizing activity, that is, may be classed as Vaughan-Williams class 1 antiarrhythmics. Labetalol is a β-blocker which also has α-blocking activity. In addition to their antihypertensive effects, β-blockers improve the myocardial oxygen supply:demand ratio and help reduce myocardial ischaemia by prolonging the period of diastole. While β-blockers are used in stable heart failure, they have the potential to worsen symptoms in some patients by reducing cardiac output. Poor peripheral circulation and Raynaud's phenomenon may be precipitated both by reduced cardiac output and block of peripheral β2 receptors. Bronchospasm caused by β2 block may be a significant respiratory side-effect in susceptible individuals, for example, asthmatics. Central nervous system effects include malaise, tiredness, and vivid dreams, particularly with lipid-soluble drugs. In insulin-dependent diabetic patients, the symptoms of hypoglycaemia may be suppressed by sympathetic block.

More than 30 β-blockers are currently available. Oral administration is common as most have good absorption and bioavailability. I.V. preparations are available for some, including atenolol, metoprolol, and esmolol. Lipid-soluble drugs, for example, metoprolol and propranolol, are generally metabolized by the liver and have shorter half-lives than water-soluble drugs, for example, atenolol, which are excreted largely unchanged in the urine. An exception is esmolol, which is metabolized by ester hydrolysis accounting for its rapid offset of action.

There is evidence that β-blockers have cardioprotective benefits when used perioperatively. Patients taking β-blockers who suffer myocardial infarction in the perioperative period are more likely to survive than those who are not. Patients on established β-blocker therapy are therefore recommended to continue treatment through the perioperative period.9 Initiation of therapy before operation is more controversial, particularly in patients with low cardiovascular risk. The POISE study evaluated the effect of commencing metoprolol at a fixed dose on the day of surgery in patients with the risk of atherosclerotic disease undergoing non-cardiac surgery. While fewer patients in the metoprolol group suffered a myocardial infarction, their risks of stroke and all-cause mortality were greater than the placebo group.10 There may, however, be a role for carefully titrated preoperative β-blockers in planned procedures.

α-Blockers

α-Blockers are used to treat hypertension in patients resistant to, or intolerant of, other treatments. Specific indications for their use in secondary hypertension include labetalol for pre-eclampsia and phentolamine in the perioperative management of phaeochromocytoma. α-Blockers are also commonly used to improve urinary flow in benign prostatic hyperplasia, for example, tamsulosin.

Most α-blockers selectively target post-ganglionic α1 Gq protein-coupled receptors leading to peripheral vasodilatation and reduced SVR. Non-selective α-blockers, for example, phentolamine and phenoxybenzamine, act at α1 and α2 receptors. Blockade of presynaptic α2 Gi-protein-coupled receptors leads to norepinephrine release with resultant tachycardia and increased cardiac output.

Labetalol is a non-selective β-blocker which also acts as an α1 adrenoceptor blocker. Therefore, it manipulates arterial pressure by acting upon multiple pathways. Adverse effects of α-block include orthostatic hypotension with a reflex tachycardic response, especially after a first dose. In patients unable to mount a tachycardic response, for instance, those taking rate-limiting drugs, this can lead to profound hypotension and syncope. Other side-effects include oedema, headache, incontinence, and drowsiness.

Calcium channel blockers

CCBs are first-line treatment for primary hypertension in patients over the age of 55 and black patients of African or Caribbean family origin. Rate-controlling CCBs (diltiazem, verapamil) are also used to manage tachyarrhythmias and angina, where their negative inotropic and chronotropic effects improve the myocardial oxygen supply:demand ratio. Some CCBs have specific non-cardiac indications, for example, nimodipine in neurosurgery to reduce cerebral vasospasm in patients after spontaneous subarachnoid haemorrhage, and verapamil in neurology to treat cluster headache.

CCBs act on l-type calcium channels present in vascular smooth muscle and in myocardial and nodal tissues. The variable affinity of the different CCBs to these different tissues determines their effects. Those with higher affinity to cardiac tissue (diltiazem, verapamil) cause negative chronotropy and inotropy. Those with higher affinity to vascular smooth muscle cause peripheral vasodilatation and reduced SVR, which may result in reflex cardiac stimulation.

Cardiovascular side-effects include reflex tachycardia which may potentiate myocardial ischaemia, disturbance of the peripheral microcirculation leading to swelling of the hands and feet, flushing, and headache. Rate-limiting agents prolong atrio-ventricular conduction and cause bradycardia; the negative inotropic and chronotropic effects may worsen heart failure.

CCBs are a chemically diverse group of drugs, which comprise phenylalkylamines, for example, verapamil; dihydropyridines, for example, amlodipine and nifedipine; and benzothiazepines, for example, diltiazem. CCBs have varying pharmacokinetic properties. Most are orally administered, although their bioavailability is generally low due to extensive first-pass metabolism. I.V. preparations are available for some drugs (verapamil, nimodipine, nicardipine), while nifedipine may be administered sublingually. Most have half-lives of <12 h, although there are exceptions, including amlodipine, which has a significantly longer half-life.

There is little evidence that commencing or continuing the use of CCBs perioperatively reduces the risk of myocardial infarction or death. While there is evidence that continued use of CCBs in the presence of β-blockers may lead to increased incidence of hypotension under anaesthesia, it is not generally recommended that CCBs be withheld before surgery.7

Diuretics

Thiazide (bendroflumethiazide, hydrochlorothiazide) and thiazide-like (chlortalidone, indapamide) diuretics are the most commonly prescribed diuretic agents used to treat hypertension. They are used in patients intolerant of CCBs and in patients with heart failure, or at risk of heart failure. They are also used as ‘add on’ drugs in patients who have not responded to first- and second-line antihypertensive treatments.1

Thiazide diuretics act on the proximal part of the distal tubule to inhibit sodium and chloride reabsorption, with resultant reduction in water reabsorption leading to diuresis. The diuretic effect is dependent upon their excretion into the renal tubule and is therefore reduced in renal impairment.

Some of the antihypertensive effect of thiazides can be attributed to their diuretic effect leading to a reduction in blood volume. However, thiazides also cause vasodilatation and reduce the responsiveness of vascular smooth muscle to vasoactive substances resulting in a reduction in SVR. One direct mechanism by which thiazides cause these effects is through opening of calcium-activated potassium channels.

Thiazide diuretics have many clinically relevant biochemical side-effects including hypokalaemia, hypercalcaemia, hyponatraemia, hypomagnesaemia, hyperglycaemia, hyperuricaemia, hypercholesterolaemia, and hypochloraemic alkalosis. Plasma volume loss may precipitate dehydration and acute kidney injury. Less common side-effects include skin rashes, photosensitivity reactions, and blood dyscrasias including thrombocytopaenia.

Aldosterone antagonists, for example, spironolactone, are recommended as fourth-line treatment of primary hypertension. The use of these drugs carries a risk of hyperkalaemia, particularly in patients with impaired renal function or who are taking other potassium-sparing agents. Loop diuretics are indicated for resistant hypertension in patients with heart failure, chronic kidney disease, and in those at risk of hyperkalaemia.

While diuretic therapy may be continued during the perioperative period, attention should be paid to the patient's fluid status and the potential for precipitating an acute kidney injury and metabolic or electrolyte abnormalities.

Other antihypertensives

Vasodilators

Directly acting vasodilators, for example, hydralazine and minoxidil, are seldom used due to their side-effect profiles. Hydralazine is used in hypertension secondary to pre-eclampsia. In addition to its antihypertensive effects, minoxidil is used topically as a treatment for male pattern baldness.

Vasodilators cause relaxation of vascular smooth muscle in resistance (arteriolar) vessels. Minoxidil achieves this via adenosine triphosphate-dependent potassium channels on smooth muscle cell membranes. Hydralazine acts through activation of adenylate cyclase, increasing intracellular cyclic guanosine monophosphate. Vasodilatation provokes reflex cardiac stimulation (which may precipitate cardiac ischaemia) and RAS activation. These compensatory responses may be offset by β-blockers or diuretics.

Vasodilator drugs are poorly tolerated. Side-effects include headache, fluid retention, and oedema. Other specific side-effects include left ventricular hypertrophy, pericardial and pleural effusions, hypertrichosis and coarsening of features with minoxidil, while peripheral neuropathy, blood dyscrasias, and a lupus-like reaction can occur with hydralazine.

Centrally acting agents

Centrally acting agents include clonidine (α2 adrenoceptor agonist), methyldopa (precursor of an α2 adrenoceptor agonist), and moxonidine (agonist at imidazoline binding sites). Their use in primary hypertension is limited to difficult to treat cases, while methyldopa is used to treat hypertension in pregnancy. The evidence base for the use of centrally acting drugs in hypertension is limited and adverse effects are common.

Clonidine is an analgesic and sedative drug which reduces the minimum alveolar concentration of inhalation anaesthetic agents. Both of these drugs cause side-effects including dry mouth and sedation. Methyldopa has immunological side-effects, including pyrexia, haemolytic anaemia, and hepatitis. Cessation of treatment with clonidine can cause rebound hypertension.

Ganglion blockers

Ganglion blockers, such as trimetaphan, antagonize acetylcholine at nicotinic receptors, including those at the adrenal cortex. Trimetaphan causes vasodilatation with a consequent rapid reduction in arterial pressure. Although ganglion blockers may be used to manage hypertensive crises or to provide hypotensive anaesthesia, their use is increasingly rare.

Declaration of interest

None declared.

MCQs

The associated MCQs (to support CME/CPD activity) can be accessed at www.access.oxfordjournals.org by subscribers to BJA Education.

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© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email:

© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email:

Which antihypertensive drug causes tachycardia?

Do ACE inhibitors cause tachycardia?

Do calcium channel blockers cause tachycardia?

Does amlodipine cause reflex tachycardia?

Does nifedipine cause tachycardia?

Can hydralazine cause tachycardia?