20

Hypertension

Learning objectives: • To understand regulation of blood pressure and • To understand management goals significance of hypertension • To appreciate use of drug therapy, patient • To familiarise oneself with blood pressure monitoring and follow-up required monitoring • To identify principles of drug therapy in • To identify drugs used in hypertension and hypertensive emergency. appreciate their characteristics • To review current guidelines for the management of hypertension

Background • drug-induced factors (e.g. oral contraceptives, corticosteroids). Hypertension is a chronic condition characterised by a sustained diastolic reading greater than or equal to 80 mmHg and a systolic reading greater than or Regulation of blood pressure equal to 120 mmHg (120/80 mmHg). Occurrence can damage blood vessels and increase probability of • Peripheral vascular resistance (depends on development of atheromatous disease. Treatment is arteriolar volume) aimed to decrease morbidity and mortality. • Cardiac output (depends on heart rate, Factors implicated in primary hypertension contractility, filling pressure, blood volume) include: • Blood pressure cardiac output peripheral vascular resistance. • age • genetics • environment Sympathetic nervous system • weight Baroreceptors present in the aorta and carotid sinus: • race.

Causes of secondary hypertension include: • increase cardiac output • increase peripheral resistance. • renal disease • pregnancy The renin–angiotensin–aldosterone system is shown • hormonal factors in Figure 20.1.

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Renin–angiotensin–aldosterone system

Vasoconstriction Angiotensinogen from liver Renin from kidney

Aldosterone from Sodium adrenal cortex retention

Angiotensin I Angiotensin II

Sodium retention in kidney

Figure 20.1 Renin–angiotensin–aldosterone system.

Risk factors Occurrence of hypertension may exacerbate: • Family history • Age • atherosclerosis • Obesity • coronary artery disease • Smoking • congestive heart failure • Lifestyle: stress, sedentary, diet • diabetes mellitus • Diabetes mellitus • insulin resistance • Hyperlipidaemia. • stroke • renal disease • retinal disease. Target organ damage due to hypertension Blood pressure measurement • Cardiovascular: constriction of arterioles and insufficient blood flow to coronary vasculature Using a sphygmomanometer (see also leads to angina, myocardial infarction; left Chapter 11) ventricular hypertrophy may occur due to increased cardiac output leading to heart • Patient should be relaxed, sitting down with arm failure. at about the level of the heart; check pressure in • Renal: arteriolar nephrosclerosis leads to both arms. polyuria, nocturia, protein and red blood cells in • Three consecutive elevated readings taken on urine, elevated serum creatinine, renal three separate occasions should be documented insufficiency. before the diagnosis of ‘hypertension’ is applied • Cerebral: decreased blood flow and decreased to a patient. oxygen supply lead to transient ischaemic • Interpretation of results: systolic reading is more attacks, cerebral thromboses, haemorrhage. important than diastolic reading; patient history • Retinal: damage to arterioles of retina leads to and family history are taken into consideration haemorrhage, visual disturbances. when deciding on line of action.

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Management goals When to refer European Guidelines for the management of • • High blood pressure (more than hypertension were issued in June 2007 by the 180/110 mmHg with signs of European Society of Hypertension jointly with papilloedema and/or retinal haemorrhage) the European Society of Cardiology.1 • Suspected phaeochromocytoma (signs Overall goal to achieve blood pressure (BP) of • include labile or postural hypotension, 140/90 mmHg. headache, palpitations, pallor and Goal takes into consideration comorbidities • diaphoresis) (e.g. in diabetes the goal is to achieve • Unusual signs and symptoms or 130/80 mmHg). symptoms that suggest a secondary cause Pharmacotherapy should consider the five • of high blood pressure. important drug classes: ACE inhibitors, angiotensin receptor antagonists, beta-blockers, calcium channel blockers and diuretics. Management of hypertension • Choice of drug therapy should depend on: – comorbidities (e.g. diabetes mellitus – ACE • Confirm diagnosis through repeated blood inhibitors or angiotensin receptor antagonists; pressure measurement metabolic syndrome – angiotensin-converting • Patient assessment for underlying cause(s) and enzyme (ACE) inhibitors, angiotensin receptor comorbidities antagonists, calcium antagonists) • Assess occurrence of target organ damage – history of clinical events (e.g. myocardial • Review treatment options infarction – beta-blockers, ACE inhibitors, • Establish treatment goals angiotensin receptor antagonists; angina • Identify and manage other risk factors (e.g. pectoris – beta-blockers, calcium channel hyperlipidaemia) blockers (avoiding short-acting • Patient follow-up. dihydropyridines); heart failure – diuretics, beta-blockers (particularly carvedilol), Reviewing treatment options ACE inhibitors, angiotensin receptor antagonists) • Pharmacotherapy or non-pharmacological – organ damage (e.g. renal dysfunction – ACE measures only? inhibitors, angiotensin receptor antagonists; • Which drug(s)? left ventricular hypertrophy – ACE inhibitors, Diagnosis and management of hypertension are shown angiotensin receptor antagonists, calcium in Figure 20.2. channel blockers). • Regardless of which drug therapy is used, monotherapy achieves blood pressure goal Cardiovascular risk assessment in only a limited number of patients. Majority of • Urine test for proteinuria and albuminuria patients require multiple drug therapy. • Blood tests: glucose, electrolytes, creatinine, • Lifestyle measures are relevant for all serum total cholesterol and high-density patients: smoking cessation, weight reduction lipoprotein (HDL) cholesterol and maintenance, reduction of excessive • ECG. alcohol intake, physical exercise, reduction of salt intake, increased fruit and vegetable Lifestyle changes intake, decreased saturated and total fat intake. • Weight reduction • Exercise Sample chapter from Lecture Notes in Pharmacy Practice 110 | Lecture Notes in Pharmacy Practice

Diagnosis of hypertension

Medical history Physical exam, diagnostic tests

High blood pressure and identified cardiovascular risk/comorbidities

Modify lifestyle Pharmacotherapy

Patient monitoring Continuing treatment

Figure 20.2 Diagnosis and management of hypertension.

• Diet (low-salt diet) blood pressure. (Note use of ambulatory blood • Smoking cessation pressure monitors to detect variation of blood • Alcohol restriction. pressure control.)

See Figure 20.3 for decision-making in management Factors influencing choice of drug of hypertension. • Contraindications to drug • Presence of target organ damage, renal disease, Potential indications for the use of diabetes or cardiovascular disease • Other coexisting disorders ambulatory blood pressure • Interactions with drugs used for other conditions monitor by the patient • Age • Unusual blood pressure variability • Occupation • White coat hypertension • Lifestyle. • Evaluation of nocturnal or drug-resistant hypertension Determining efficacy of treatment over 24 hours Use of antihypertensive drugs • • Diagnoses and treatment of hypertension in • Initiate drug therapy at a low dose pregnancy. • Consider multiple drug therapy • Change to different class of drugs if drug is not producing effect on blood pressure levels or if Drug therapy side-effects are a significant problem • Use formulations that provide a 24-hour control: • Diuretics: reduce blood volume better adherence and ensure control of blood • Sympatholytics: reduce ability of sympathetic pressure in early morning when there is surge of system to raise blood pressure

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Overall cardiovascular Decision about drug therapy risk of the patient

Examples c alculation of risk Computer programs/algorithms, e.g. Coronary Risk Prediction Charts Family history, (British Hypertension Society)a other conditions

Figure 20.3 Decision-making in management of hypertension. aTo be found in the BNF.2

• Calcium channel blockers: reduce peripheral • Act in the distal convoluted tubule resistance • Are weak diuretics and in fact may be found in • ACE inhibitors, angiotensin II antagonists: combination products with thiazides. reduce peripheral resistance

Table 20.1 Comparison of bendroflumethiazide Diuretics and indapamide Create a negative sodium balance resulting in a • Bendroflumethiazide Indapamide reduction of blood volume • Thiazides (e.g. bendroflumethiazide, indapamide) Half-life (hours) 3–4 14 Loop diuretics (e.g. furosemide) are used mainly • Duration of effect 6–12 24–36 in pulmonary oedema due to ventricular failure, (hours) chronic heart failure (see also Chapter 22). a • Potassium-sparing diuretics (e.g. amiloride Dose (mg) 2.5 2.5 ( hydrochlorthiazide), spironolactone) aTo be administered in the morning to reduce nocturnal need for • Caution: hypokalaemia. urination. Thiazide diuretics O • Reduce sodium and water retention in the distal O O O S S H convoluted tubule in the kidney resulting in a N H2N reduction of the peripheral resistance F C N Cause loss of potassium and magnesium salts 3 • Bendroflumethiazide • Potassium supplementation should be considered H • Maximal hypotensive effect is reached at relatively low doses.

O O Bendroflumethiazide and indapamide are com- O pared in Table 20.1 and their chemical structures S N N H N shown in Figure 20.4. 2 H CI Potassium-sparing diuretics Indapamide • Retain potassium and therefore no need to Figure 20.4 Chemical structures of bendroflumethiazide consider potassium supplementation and indapamide.

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Table 20.2 Side-effects of diuretics Drug interactions • Potassium-sparing diuretics: ACE inhibitors since Side-effect Key monitoring parameters ACE inhibitors may cause hyperkalaemia Hypokalaemia Fatigue, weakness, bilateral calf pain, • With NSAIDs: hypotensive effect is inhibited. palpitations, gastrointestinal upset

Dehydration Tachycardia, dizziness upon standing up, thirst, postural hypotension, decreased skin Beta-blockers turgor • Competively block beta receptors of the Hyperuricaemia Feeling of fullness in arch of foot, sympathetic system resulting in slowing of the occasionally painful joint – development of heart, reduction in the force of contractions and gout (usually big toe), high serum uric acid lengthening of diastole.

Hyperlipidaemia High serum cholesterol and triglycerides • Side-effects: bradycardia, heart failure, hypotension, bronchospasm, peripheral Impaired glucose High serum glucose vasoconstriction, fatigue, depression, vivid tolerance dreams. • Cautions/contraindications: asthma, COPD, peripheral vascular disease, Raynaud’s Side-effects of diuretics phenomenon, heart block, diabetes mellitus The side-effects of diuretics are listed in Table 20.2. (they may mask symptoms of hypoglycaemic Hypercalcaemia and impotence may also be attacks). reported as side-effects. For potassium-sparing diuretics, hyperkalaemia Various beta-blockers are compared in Table 20.3 rather than hypokalaemia may occur. Key moni- (see also Chapter 21) and their chemical structures toring parameters to identify occurrence of hyper- are shown in Figure 20.5. kalaemia include gastrointestinal hyperactivity, Propranolol has a high octanol/buffer partition muscle weakness and cramps. coefficient indicating a high lipophilicity. It enters the central nervous system better than other beta- blockers. Its primary clearance route is through the Patients at risk of developing electrolyte liver while more hydrophilic agents such as atenolol imbalance are cleared primarily through the kidneys. This should be kept in mind when selecting a drug in Patients with vomiting • patients with renal or liver disease. • Patients with diarrhoea • Elderly patients Intrinsic sympathomimetic activity • Patients with ascites due to liver cirrhosis • Patients with oedema due to nephritic Beta-blockers act by stimulating beta receptors when syndrome background sympathetic activity is low and blocking • Patients receiving parenteral fluid therapy. them when activity is high.

• Less resting bradycardia and possibly less cold extremities Cautions and contraindications of diuretics • Extrapolation in practice: limited. • Gout Side-effects • Renal disease • Diabetes The side-effects of beta-blockers are summarised in • Electrolyte imbalance. Table 20.4.

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Table 20.3 Comparison of beta-blockers

Drug Cardioselectivitya Lipid solubility Intrinsic sympathomimetic activity Half-life (hours) Starting dose

Atenolol Low 0/low 6–7 50 mg once daily

Carvedilol – High 0/low 6–10 12.5 mg once daily

Labetalol – Low 0/low 8 100 mg twice daily with food

Propranolol – High 0/low 3–6 80 mg twice daily

aImplying lesser effects on airways and lower risk of precipitating bronchospasm.

OH H Table 20.4 Side-effects of beta-blockers O N O Side-effect Key monitoring parameters

H N Coldness of extremities 2 Atenolol (mol. wt 266) Central nervous system Nightmares, sedation, hallucinations OH H Congestive heart failure Dyspnoea, orthopnoea, weight gain, O N ankle oedema, tachycardia

Bronchospasm Wheezing Propranolol (mol. wt 259) Hyperglycaemia Polyuria, polydipsia

Hypoglycaemia Increased sweating OH H HN O N O • Rapid onset of action O • Side-effects: hypotension (especially first dose), Carvedilol (mol. wt 406) hyperkalaemia, cough, renal impairment • Cautions: patients receiving diuretics, peripheral vascular disease, renovascular disease, severe or O OH H symptomatic aortic stenosis, hypertrophic N H2N cardiomyopathy • Check renal function prior to initiating therapy HO Labetalol (mol. wt 328) • Monitor renal function during therapy • Care in elderly patients since they are at risk of Figure 20.5 Chemical structures of atenolol, propanolol, renal side-effects carvedilol and labetalol. • Avoid concomitant NSAID use in patients at risk of renal side-effects since concomitant use Angiotensin-converting enzyme increases risk and antagonises hypotensive effect inhibitors of ACE inhibitors. ACE inhibitors decrease formation of angiotensin II, resulting in decreased vasoconstriction and decrease Some ACE inhibitors are compared in Table 20.5. in aldosterone production, which in turn results in Captopril (see Figure 20.6) contains a sulph- decreased fluid retention. hydryl group which serves as the zinc-binding group

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Table 20.5 Some ACE inhibitors compared • Dehydrated patients Drug Half-life (hours) Starting dose • Patients on a low-sodium diet Captopril 2–3 12.5 mg twice daily • Dialysis patients • Elderly patients. Enalapril 11 5 mg once daily

Lisinopril 12 10 mg once daily Patients are advised to start first dose at night to avoid consequences of hypotension. Perindopril 25–20 4 mg once daily

Ramipril (for active 13–17 1.25 mg once daily metabolite, ramiprilat)

ACE, angiotensin-converting enzyme. COOEt N N COOEt H O COOH HS N N Enalapril (mol. wt 376) H O COOH H2N Captopril (mol. wt 266) COOH Figure 20.6 Chemical structure of captopril. N N that is required for ACE inhibitory effects. The pres- H O COOH ence of the sulphhydryl group is associated with a Lisinopril (mol. wt 406) higher incidence of skin rashes and taste disturbances. Also the sulphhydryl component may form a disul- phide which results in a short half-life for the product. COOEt Enalapril, lisinopril, perindopril and ramipril (see N Figure 20.7) are dicarboxylate-containing ACE N inhibitors that do not feature a sulphhydryl group. H O COOH The presence of large hydrophobic heterocyclic rings Perindopril (mol. wt 368) in the N-ring of perindopril, ramipril, moexipril, quinapril and trandolapril result in increased potency and longer half-life when compared with enalapril and COOEt lisinopril. This feature also results in enalapril and N lisinopril lacking lipid solubility. Perindopril shows the N highest oral bioavailability, followed by trandolapril. H O COOH Ramipril (mol. wt 417) Side-effects Chemical structures of enalapril, lisinopril, The side-effects of ACE inhibitors are summarised in Figure 20.7 perindopril and ramipril. Table 20.6.

Patients at risk of hypotension with ACE Angiotensin II receptor antagonists inhibitors (ARBs)

• Those on concomitant diuretics These are specific angiotensin II receptor antagonists, • Patients with heart failure which thus block the vasoconstrictor and aldosterone- secreting effects of angiotensin II.

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Table 20.6 Side-effects of ACE inhibitors HO CI Side-effect Key monitoring parameters N Hypotension Usually occurs in volume-depleted patients N N N Hyperkalaemia Usually occurs if concomitant use of potassium HN N supplement or potassium-sparing diuretic Losartan (mol. wt 423) Renal effects Cough H C ACE, angiotensin-converting enzyme. 3 N

N Do not inhibit breakdown of bradykinin, so less • H3C likely to cause cough as a side-effect Used as an alternative therapy to ACE inhibitors • N • Side-effects: hypotension, dizziness, N COOH hyperkalaemia Telmisartan (mol. wt 515) • Caution: renal artery stenosis.

ARB half-lives and starting dosages are listed in CH3 H3C Table 20.7 and their chemical structures in Figure O 20.8. COOH H3C

HOOC N Calcium channel blockers N N HN N • Examples: dihydropyridines: nifedipine, amlodipine Valsartan (mol. wt 436) • Interfere with the opening/closing of calcium channels in cardiac, vascular and smooth muscle Figure 20.8 Chemical structures of losartan, telmisartan cells and valsartan. • The dihydropyridines (e.g. nifedipine, amlodipine) cause peripheral vasodilatation and • Side-effects: palpitations, flushing, oedema, have little direct effect on heart compared with headache, dizziness verapamil and diltiazem (which are other types • Sustained-release preparations or long-acting of calcium channel blockers) drugs such as amlodipine are preferred to • Rapid onset of action decrease risk of myocardial infarction • Should be avoided in heart failure • See also Chapter 21. • Upon withdrawal may exacerbate angina Last line drugs

Table 20.7 Angiotensin II receptor antagonist These are summarised in Table 20.8. half-lives and starting dosages Rilmenidine Half-life (hours) Starting dose This drug selectively binds to I -imidazoline receptors Losartan 2 50 mg daily 1 in the brainstem. The receptors influence adrenergic Telmisartan 20 40 mg daily vasomotor tone involved in blood pressure regula- tion. I -imidazoline receptors are also available in the Valsartan 5–9 80 mg daily 1 kidneys.

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Table 20.8 Last line drugs Table 20.9 Contraindications to drug therapy

Drug Side-effects Drug class Contraindications

Centrally acting drugs ACE inhibitors Renovascular disease Methyldopa, moxonidine Depression Angiotensin II receptor Renovascular disease Vasodilatation antagonists Vasodilator antihypertensive drugs Beta-blockers Asthma, chronic obstructive Minoxidil Potent vasodilator pulmonary disease, heart block Marked fluid retention Hirsutism Calcium channel blockers Heart block, heart failure Reflex tachycardia Thiazide diuretics Gout Adrenergic neuron blockers Guanethidine Severe postural hypotension Diarrhoea

Alpha-adrenoceptor blockers Table 20.10 Cautions to use of drug therapy Doxazosin (see also Chapter 41) Postural hypotension Dizziness Drug Caution Vertigo Beta-blockers Heart failure, peripheral vascular disease, diabetes

ACE inhibitors/ARBs Renal impairment, peripheral vascular disease

Rilmenidine is an antihypertensive agent with a ACE, angiotensin-converting enzyme; ARBs, angiotensin II central action on the brainstem and a peripheral receptor antagonists. activity in the kidney. Its characteristic is that it is selective for the I1-imidazoline receptors rather than also interacting with cerebral alpha2-adrenergic Potential problems with non- receptors. prescription medicines in hypertension • Available as tablets 1 mg, dosage regimen: one tablet per day Antacids (high sodium content) • Contraindications: severe depression, renal • Cold preparations for systemic use containing insufficiency (creatinine clearance • sympathomimetics 15 mL/min) NSAIDs • Side-effects: rare; asthenia, palpitations, • Potassium-containing preparations (e.g. salt insomnia. • substitutes, potassium citrate indicated for cystitis). Contraindications and cautions

The contraindications and cautions to use of drug therapy are summarised in Tables 20.9 and 20.10. Pharmacist patient review • To monitor blood pressure Drug interactions • To provide patient support with drug therapy and lifestyle modifications Some of the common drug interactions with anti- hypertensive drugs are listed in Table 20.11.

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Table 20.11 Common drug interactions with antihypertensive drugs

Drug class Interacting drug Interaction

Thiazide diuretics NSAIDs Decreased hypotensive effect Digoxin Digoxin toxicity if hypokalaemia occurs

Beta-blockers Antiarrhythmics Bradycardia Sympathomimetics Severe hypertension NSAIDs Decreased hypotensive effect

ACE inhibitors NSAIDs Hyperkalaemia

ACE inhibitors and angiotensin II receptor blockers K supplementation Hyperkalaemia K-sparing diuretics Hyperkalaemia

ACE, angiotensin-converting enzyme; NSAIDs, non-steroidal anti-inflammatory drugs.

tension, 140/90 mmHg developing during pregnancy in a woman whose blood pressure was previously To discuss symptoms and medication • normal – and eclampsia – occurrence of convulsions (identify unwanted drug effects, any other caused by hypertension. drugs taken by patient for other disease states) • To evaluate need for patient referral to • Methyldopa is the drug of choice. prescriber (based on laboratory test • Calcium channel blockers (amlodipine and results and/or the presence of other nifedipine): manufacturer advises avoidance but symptoms) risk of uncontrolled maternal hypertension • To consider use of other drugs that reduce should be balanced against risk of use of drug. cardiovascular risk (aspirin and statin • Beta-blockers tend to cause birth of smaller therapy). babies. • ACE inhibitors and angiotensin II receptor blockers cannot be used – they may damage the fetus and cause problems in the neonate. Drug therapy in the elderly • Diuretics avoided because of decreased intravascular volume. • Calcium channel blockers indicated as first-line agents • Diuretics less effective when there is Phaeochromocytoma compromised renal function • Beta-blockers less potent in the elderly Phaeochromocytoma is a tumour of chromaffin tissue • Effect of ACE inhibitors may be decreased due to of the adrenal medulla or sympathetic paraganglia. lower renin levels. • Leads to uncontrolled and irregular secretion of adrenaline and noradrenaline Hypertension in pregnancy • Causes raised blood pressure, increased heart rate, palpitations, headache Two conditions associated with hypertension in preg- • Use phenoxybenzamine, alpha-blockers or beta- nancy are pre-eclampsia – pregnancy-induced hyper- blockers.

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Hypertensive emergency • Side-effects: hypotension, nausea and vomiting; if treatment is for more than 24–28 hours, This is a severe elevation in blood pressure with a thiocyanate toxicity (it reacts with sulphhydryl diastolic above 120–130 mmHg and the presence of groups in blood and tissue producing acute or on-going end-organ damage, with cerebral thiocyanate). infarction and pulmonary oedema being the most common occurrences of end-organ damage. Labetalol An alpha- and beta-adrenergic blocking drug. This may be a medical emergency and requires • • Produces a reduction in peripheral vascular prompt reduction of blood pressure within • resistance, blood pressure and heart rate minutes to 1 hour Rapid onset of action: 5 minutes Conditions that predispose to hypertensive • • Duration of effect: 6 hours or longer emergency include phaeochomocytoma, renal • Dose: 0.5–2 mg/min continuous infusion vascular disease, head injury, severe burns, • Advantage: available for parenteral and oral eclampsia • administration and so allows easy conversion Goal of treatment: diastolic pressure • from intravenous administration to oral 100–119 mmHg. therapy Major complications that occur in a hypertensive • Side-effects: orthostatic hypotension, nausea and emergency include: vomiting, dizziness, flushing, headache • Contraindications: asthma, congestive heart • angina failure, bradycardia. • myocardial infarction • congestive heart failure Diazoxide • cerebral infarction • Causes a vasodilator effect on the arterioles • intracranial haemorrhage. resulting in decreased peripheral resistance. It also inhibits the secretion of insulin by the beta Management of hypertensive crisis cells of the pancreas • Available for parenteral administration • Very rapid fall in blood pressure can cause • Onset of action within 2–5 minutes with a reduced cerebral perfusion leading to: cerebral preliminary rise in blood pressure immediately infarction, blindness, renal function after administration deterioration, myocardial ischaemia • Caution: ischaemic heart disease, renal • Oral antihypertensive drugs are used to decrease impairment blood pressure slowly • Side-effects: tachycardia, hypotension, • Parenteral treatment: rarely adopted; drug of hyperglycaemia, sodium and water retention choice is nitroprusside. • Patient monitoring: blood pressure, blood Nitroprusside glucose levels particularly in patients with diabetes. • Direct-acting arterial and venous vasodilator that is available for parenteral administration • Immediate onset of action • Antihypertensive effect disappears within 2–5 Practice summary minutes after discontinuation • Starting dose: 0.5–10 micrograms/kg per min via • The regulation of blood pressure depends on the continuous infusion peripheral resistance and the cardiac output. • Caution: hypothyroidism, hyponatraemia, These factors are affected by the sympathetic ischaemic heart disease, impaired cerebral nervous system and the renin–angiotensin– circulation, elderly, hypothermia aldosterone system.

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• Drugs that are used as antihypertensives aim to Answers reduce blood volume (diuretics), decrease sympathetic activity (beta-adrenoceptor 1 Atenolol and enalapril are compared in Table blockers), reduce peripheral resistance (calcium 20.12. channel blockers) and affect the renin– 2 Gout, renal disease, diabetes, electrolyte angiotensin–aldosterone system (ACE inhibitors, imbalance. angiotensin II antagonists). 3 Naproxen is a non-steroidal anti-inflammatory • Antihypertensives may be used in monotherapy drug that causes salt and fluid retention, thus or as combination therapy. decreasing the hypotensive effect of thiazide diuretics. 4 Bendroflumethiazide is a thiazide diuretic that Questions reduces sodium and water retention in the distal convoluted tubule in the kidney, creating a 1 Compare atenolol and enalapril considering negative sodium balance, resulting in a reduced indications, dosage regimen, side-effects and blood volume and a reduced peripheral contraindications. resistance. It is indicated in hypertension and 2 Name two conditions when thiazide diuretics oedema. should be used with caution or are 5 In a 58-year-old patient diagnosed with contraindicated. hypertension and with a history of diabetes 3 What is the clinical implication when a patient mellitus an angiotensin-converting enzyme who is receiving a thiazide diuretic is also (ACE) inhibitor is indicated as first-line started on naproxen? treatment. ACE inhibitors should be used with 4 Giving reasons for your answer, explain when caution in renovascular disease; however, in bendroflumethiazide is indicated. diabetes they have a renoprotective effect. 5 Describe drug therapy that should be considered Renal function should be checked prior to as first line in a 58-year-old patient diagnosed initiating therapy and monitored during therapy. with hypertension who has a history of diabetes ACE inhibitors may cause profound first-dose mellitus. What other preventive drug therapy hypotension, so first doses should be given at could be considered? night. Potassium levels must be monitored.

Table 20.12 Comparison between atenolol and enalapril

Generic name Atenolol Enalapril

Mode of action Cardioselective beta-blocker. Works by selectively ACE inhibitor which decreases the production of blocking the beta receptors in the sympathetic nervous angiotensin II, a potent vasoconstrictor, and also system decreases aldosterone production and hence fluid retention. These actions lower the blood pressure

Indications Hypertension, angina, myocardial infarction, arrhythmia Hypertension, heart failure

Dosage regimen Once daily Once daily

Side-effects Bronchospasm, bradycardia, heart failure, hypotension, Profound first-dose hypotension, persistent dry cough, peripheral vasoconstriction, fatigue, depression, vivid renal impairment, hyperkalaemia, skin rashes dreams

Contraindications Asthma and chronic obstructive pulmonary disease, Pregnancy, renovascular disease, hypersensitivity heart block, peripheral vascular disease, diabetes

ACE, angiotensin-converting enzyme.

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Persistent cough may be a problematic side- the British Hypertension Society, 2004–BHS IV. J Hum effect. Angiotensin II receptor antagonists do Hypertens 18: 139–185. National Institute for Health and Clinical Excellence (2006). not inhibit bradykinin, have fewer side-effects Hypertension. http://www.nice.org.uk/CG034. than ACE inhibitors and are indicated when patients are intolerant to ACE inhibitors due to the cough side-effect. Other preventive drug References therapy that can be considered to reduce cardiovascular risk includes low-dose aspirin 1 Mancia G, de Backer G, Dominiczak A et al., guidelines for the management of arterial hypertension. J Hyper- and statin therapy. tens 2007; 25: 1105–1187. 2 Joint Formulary Committee. British National Formulary, 57th edn. London: British Medical Association and Further reading Royal Pharmaceutical Society of Great Britain, 2009.

Williams B, Poulter N R, Brown M J, Davis M, McInnes Acknowledgements G T, Potter J F et al. (2004). Guidelines for management of hypertension: report of the fourth working party of Bernard Coleiro, Consultant Physician, Department of Medicine, Mater Dei Hospital, Malta

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