ADD-ONS / MEDICATION

Antihypertensive drugs

David Goldemund M.D.
Updated on 11/07/2024, published on 09/07/2024
  • antihypertensive drugs are used to manage hypertension and include ACE inhibitors, ARBs, beta-blockers, calcium channel blockers, diuretics, and alpha-blockers
  • standard doses of oral medication for outpatients are summarised in this text
  • intravenous antihypertensive drugs are discussed in the chapter on hypertensive crisis

ACE inhibitors

  • ACE inhibitors block the ACE (Angiotensin Converting Enzyme), preventing the formation of angiotensin II (AT II).
  • they effectively reduce BP even in patients with carotid atherosclerotic disease without adversely affecting cerebral blood flow.
  • other positive effects of ACE inhibitors:
    • vaso- and cardioprotective effect (improvement of coronary perfusion, reduction of LV hypertrophy)
    • nephroprotective effect (beneficial for diabetics)
    • beneficial effect on glucose metabolism
    • decrease of fibrinogen level, decrease of PAI1, and increase of tPA level
    • sympathetic inhibition
  • always monitor renal function and potassium levels during treatment;  if creatinine increases by ≥ 30%, ACE inhibitors should be discontinued

Adverse effects

  • dry irritating cough, sometimes very bothersome and leading to discontinuation of ACE inhibitors (due to slowed breakdown of bradykinin and subsequent pulmonary congestion) ⇒ switch to sartan if intolerable
  • postural hypotension
  • hyponatremia
  • allergic reactions
  • interaction with NSAIDs (reduced effect of ACE inhibitors)

Contraindications

  • bilateral renal artery stenosis
  • pregnancy and lactation
    • relative CI in fertile women
  • hypersensitivity to ACE inhibitors
  • hyperkalemia
  • porphyria
  • history of angioneurotic edema
Long half-life Initial dose Maintenance dose
perindopril (PRESTARIUM, PRENESSA)

  • half-life of 30-120 hours
  4-5 mg once daily 4-16 mg once daily
ramipril (TRITACE, RAMIL, ALTACE)

  • if needed, double the dose at 2 to 3-week intervals
  • usual maintenance dose: 2.5 or 5 mg ramipril daily;  instead of increasing the dose above 5 mg, consider adding diuretics or calcium channel blockers
  • half-life of 13-17 hours
 2.5 mg once daily 2.5-10 mg once daily
(or in divided doses)
fosinopril (MONOPRIL) 10 mg once daily 10-40 mg once daily
Medium half-life
enalapril (ENAP, VASOTEC)

  • half-life ~ 11 hours
  • in renal insufficiency, prolong administration intervals, or reduce dose
 2.5-5 mg once or twice daily 10-40 mg once or twice daily
Short-acting ACE-I
captopril (TENSIOMIN, CAPOTEN)

  • half-life 2-3 hours; mainly used for acute BP reduction
 6.25-12.5 mg three times daily

Sartans (ARB)

  • Angiotensin II Receptor Blockers (ARBs) or sartans are antihypertensive agents that can be used as initial treatment of hypertension (the same indications as ACE inhibitors)
  • they do not cause cough and generally have a low risk of side effects
  • renal function must be monitored during therapy; in combination with potassium supplements or potassium-sparing diuretics may cause hyperkalemia

Renin-Angiotensin-Aldosterone System (RAAS)

  • the renin-angiotensin-aldosterone system (RAAS) is a significant homeostasis system that protects circulation during changes in salt and water concentration
  • the key agent is renin, which cleaves angiotensinogen (produced in the liver) to angiotensin I
  • angiotensin I is activated by ACE to angiotensin II, which causes arteriolar vasoconstriction in the kidney and systemic circulation, sodium reabsorption in the proximal nephron segment, and stimulates aldosterone secretion in the adrenal cortex leading to sodium retention
  • RAAS thus not only maintains salt and water homeostasis but can also contribute to the development of hypertension

Side effects

  • tachycardia, bradycardia
  • hypotension
  • edema (arms, legs, lips, tongue, or throat)

Contraindications

  • pregnancy
  • hyperkalemia
  • renal artery stenosis (may cause kidney failure)
Sartan Initial dose in hypertension treatment Maintenance dose
losartan
(COZAAR, LOZAP)		 50 mg daily 25-100 mg
once daily or divided into two doses
valsartan
(VALZAP, DIOVAN)		 80-160 mg daily 80-320 mg daily
irbesartan
(AVAPRO, IRBEC)		 150 mg daily 150-300 mg daily
candesartan
(ATACAND, CARZAP)		 8 mg daily 8-32 mg daily
olmesartan
(BENICAR)		 20 mg daily 20-40 mg daily
telmisartan
(MICARDIS, TEZEO)		 40 mg daily 20-80 mg daily
eprosartan
(TEVETEN)		 600 mg daily 400-800 mg daily

Betablockers

  • beta-blockers (BB) slow down heart rate, reduce myocardial strain, and decrease myocardial oxygen consumption
  • the main use of BB is in combination therapy, especially for hypertension associated with manifest CAD and/or chronic heart failure or significant left ventricular dysfunction
  • BBs are divided into cardioselective and non-selective
    • cardioselective BBs mainly affect receptors in the heart
    • non-selective BBs have more pronounced effects on other organs

Adverse effects

  • bradycardia or AV block due to their negative chronotropic effect
  • bronchospasms (especially with non-selective BBs)
  • negative impact on lipid and carbohydrate metabolism
  • induce peripheral vasoconstriction

Contraindications

  • bronchial asthma
  • 2nd and 3rd degree AV block
  • other bradyarrhythmias
  • relative contraindication is peripheral arterial disease (⇒ vasoconstriction)
Betaxolol (LOKREN) Initial dose Maintenance dose
  • no dose adjustment is required for patients with renal failure
  • for patients on dialysis, the recommended dose is 10 mg/day
  • gradual dose reduction/increase is recommended (1-2 weeks) to avoid AEs
 10 mg once daily 10-20 mg once daily
Bisoprolol (CONCOR, CONCOR COR, MONOCOR, EMCOR)
  • hypertension, CAD (angina pectoris), palpitations
  • gradual dose reduction/increase is recommended (1-2 weeks) to avoid AEs
 2.5-5 mg once daily 10-20 mg once daily
Metoprolol (VASOCARDIN, BETALOC ZOK, LOPRESSOR, CORVITOL)
  • immediate and extended-release forms are available
  • arrhythmias: initially 50 mg twice daily, up to 200 mg daily
  • migraine prophylaxis: 100-200 mg daily in two divided doses
  • palpitations: 100 mg daily
 25-100 mg once daily
(extended-release form)		 100-200 mg once daily
Carvedilol (CORYOL, ATRAM, COREG, DILATRENT, CARVIL, etc.) 
  • non-selective BB without intrinsic sympathomimetic activity
  • hypertension: initial dose 12.5 mg once daily for the first 2 days
  • CAD: 12.5 mg twice daily for 2 days, then 25 mg twice daily
  • heart failure: initial dose is 3.125 mg twice daily for 2 weeks. Then slowly increase at intervals of at least two weeks up to a dose of   2x 25 mg
 12.5 mg once daily
6.25 mg twice daily		 25-50mg per day
(divided into two doses)

Calcium-channel blockers (CCB)

  • do not adversely affect lipid and glucose metabolism
  • do not cause bronchoconstriction and positively influence renal blood flow and peripheral circulation
  • suitable for treating hypertension in the elderly and isolated systolic hypertension
  • verapamil and diltiazem are not suitable for treating hypertension accompanied by heart failure or atrioventricular conduction disorders due to their negative inotropic and chronotropic effects
  • most common side effects: flushing, peripheral edema
  • relative contraindications:
    • tachyarrhythmias
    • heart failure
  Initial Dose
 Maintenance dose
amlodipine
AGEN, APO-AMLO, ZOREM, NORVASC
  • hypertension, chronic stable angina pectoris
  • caution in liver and heart failure
  • monitor for peripheral edema
 2.5-5 mg once daily 5-10 mg once daily
lercanidipine
KAPIDIN, ZANIDIP
  
  • lower risk of peripheral edema
  • take at least 15 minutes before a meal
 10 mg once daily 10-20 mg once daily
nitrendipine
LUSOPRESS
  
  • second-generation CCB, long-lasting effect, taken once daily
 10 mg once daily 10-20 mg once daily
felodipine
PRESID, PLENDIL
 2.5-5 mg once daily 5-10 mg once daily (max 20 mg)

Diuretics

Loop diuretics (furosemide)
  • used as an antihypertensive only in significantly reduced GFR (< 0.5 ml/s/1.73 m²) and in hypertensive crisis
  • used to treat hypertension associated with congestive heart failure
  • may cause a large loss of fluids, sodium, and potassium ⇒ risk of hypokalemia
  • available in tablet and IV forms
Distal diuretics (hydrochlorothiazide, indapamide)
  • used in the therapy of milder forms of heart failure and in combination therapy
  • cause ion (K, Na) and fluid losses, but not as dramatic as loop diuretics
  • have a negative impact on glucose metabolism
Potassium-sparing diuretics (amiloride, spironolactone)
  • used in resistant hypertension when even triple therapy is not effective
  • conservative treatment of primary hyperaldosteronism
  • associated with a risk of hyperkalemia (e.g., when combined with ACE inhibitors)
Loop diuretics
furosemide (FUROSEMID)

  • mainly indicated for edema and heart failure
 20-40 mg twice daily 20-80 mg twice daily
Thiazide (distal) diuretics
hydrochlorothiazide (HYDROCHLOROTHIAZIDE)

  • severe renal (creatinine clearance < 30 ml/min) and liver impairment
  • severe Na+ and K+ disturbances
  • pregnancy or lactation
 12.5 mg daily 12.5-50 mg daily
indapamide (INDAPAMID) 1.25 – 2.5 mg once daily 2.5-5 mg daily
Potassium-sparing diuretics
amiloride is commonly used in combination with HCT  – 5/50 mg (MODURETIC,  LORADUR, RHEFLUIN)

  • hyperkalemia (> 5.5 mmol/l)
  • other antikaliuretic therapy
  • potassium supplementation
  • renal insufficiency (anuria, acute renal failure, severe progressive kidney disease, and diabetic nephropathy)
 5/50 mg daily 5/50 mg daily
spironolactone (SPIRONOLACTONE, VEROSPIRON, ALDACTONE)

  • aldosterone antagonist
  • chronic heart failure (NYHA III-IV) as an add-on treatment to standard therapy
  • hypertension – add-on therapy
  • hyperkalemia
  • pregnancy
  • renal insufficiency
 25 mg daily 25-50 mg daily (hypertension)
eplerenone (SELETRA, EPLERON, INSPRA)

  • selective aldosterone receptor antagonist
  • lower incidence of gynecomastia and breast pain compared to spironolactone due to its selectivity for mineralocorticoid receptors over androgen and progesterone receptors
 25-50 mg daily 25-50 mg daily

Alpha-1 blockers

  • alpha-1 blockers, also known as alpha-1 adrenergic antagonists, are a class of antihypertensive agents that work by blocking alpha-1 receptors on blood vessels. This results in vasodilation and a subsequent decrease in blood pressure
  • used primarily for the treatment of high blood pressure and benign prostatic hyperplasia

Adverse effects

  • orthostatic hypotension
  • reflex tachycardia
  • nasal congestion
  • headaches
  • fatigue

Contraindications

  • known hypersensitivity or allergic reactions to alpha-1 blockers or any components of the formulation
  • severe hepatic impairment – use with caution
  • history of orthostatic hypotension
  • severe heart failure or other significant cardiac conditions – use with caution
  • concurrent use with phosphodiesterase-5 (PDE-5) inhibitors
  Initial dose Maintenance dose
doxazosin (CARDURA, ZOXON, DOXAZOSIN)

  • usually taken in the morning or evening
 1 mg once daily
 2-8 mg once daily
(can be increased gradually based on patient response)
terazosin (TERAZOSIN)

  • preferably taken at night
  • if a thiazide diuretic or other antihypertensive is added, the dose of terazosin should be reduced or discontinued, with re-titration if necessary
  • monitor patients closely for orthostatic hypotension and dizziness after the first dose

1 mg once daily

1-5 mg once daily
maximum dose 20 mg once daily

Centrally acting agents

Centrally-acting antihypertensive drugs reduce blood pressure by acting on the CNS. They inhibit sympathetic outflow, leading to vasodilation and decreased cardiac output.

Medications with central and peripheral effects on alpha receptors Initial dose Maintenance dose
urapidil (EBRANTIL)  30 mg twice daily 60-180 mg daily
divided into two doses
Alpha2 adrenergic agonist
methyldopa (DOPEGYT) 

  • discontinuation of methyldopa during pregnancy is not necessary in hypertensive women previously treated with methyldopa; it is excreted in breast milk – discontinue during breastfeeding!
  • the daily dose can be increased by 250 mg every two days until appropriate blood pressure reduction is achieved
  • the daily dose can be then reduced by 250 mg every two days to reach the maintenance dose
 250 mg once daily 0,5 – 2 g daily
divided into two to three doses
clonidine (CATAPRES) 

  • initial dose 0.1 mg twice daily; gradually increase in increments of 0.1 mg per day at weekly intervals
  • maximum daily dose: 2.4 mg 
  • avoid abrupt discontinuation
  • side effects: sedation, dry mouth, bradycardia, rebound hypertension upon abrupt withdrawal
  • caution is advised in patients with severe coronary insufficiency, recent myocardial infarction, or cerebrovascular disease
 0.1 mg twice daily 0.2-0.6 mg daily
divided into two doses
Imidazoline receptor agonists
rilmenidine (TENAXUM, RILMENIDIN TEVA)

  • selective imidazoline receptor agonist
  • fewer CNS side effects compared to clonidine
 1 mg once daily (morning) 1-2 mg daily
(single 2mg dose, or 1 mg twice daily)
moxonidine (CYNT, MOXOGAMMA)

  • maximum daily dose, given in two divided doses, is 0.6 mg
  • moxonidine has some activity on alpha-2 adrenergic receptors
 0.2 mg once daily 0.2-0.4 mg daily
as a single dose or divided into two doses

Combination of drugs

  • combination therapy for hypertension is favored because of its higher efficacy and better tolerability and compliance
    • with monotherapy, only 20-30% of patients achieve target levels
  • initial dual therapy is recommended for patients with SBP > 160 mm Hg / DBP > 100 mm Hg and individuals at high cardiovascular risk
  • adequate blood pressure control can be achieved in most hypertensive patients with a combination of 2-3 antihypertensive drugs
    • combining drug classes provides more effective blood pressure control than doubling the dose of a single agent (which often leads to adverse effects)
    • many patients require at least a triple combination
  • prerequisites for effective combination therapy: drugs with similar duration of antihypertensive effect and, ideally, different mechanisms of action with additive impact on blood pressure reduction without increasing the incidence of adverse effects
  • the most common dual combination is ACE-I/sartan + CCB/diuretics
  • a fixed combination of ACE-I + CCB is the first choice in patients with hypertension and metabolic disorders (dyslipidemia, metabolic syndrome, impaired glucose tolerance, or diabetes), in patients with organ complications or associated cardiovascular and renal diseases
    • improved patient compliance with treatment, better tolerability, and efficacy, lower cost
    • both components have a vasodilator effect, which is beneficial in elderly hypertensive patients with increased peripheral resistance, endothelial dysfunction, atherosclerotic lesions, and reduced vascular compliance
    • more effective than its individual components in monotherapy (e.g., TEAMSTA-5 study)
    • more effective than ACEI + thiazide diuretic combination in preventing cardiovascular events (ACCOMPLISH trial)
    • if ACE-I is not tolerated, an ARB can be used instead
  • a diuretic should be part of the triple combination
    • the optimal combination is ACEI/ARB + CCB + thiazide diuretic
    • the fourth drug should be a BB, alpha-blocker, or spironolactone
    • in multiple combinations, centrally acting drugs can be added: rilmenidine, moxonidine, urapidil
  • not recommended combinations:
    • BB + diuretic (accumulation of adverse metabolic effects)
    • ACE-I + ARB (hyperkalemia, renal insufficiency)
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Antihypertensive drugs
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