1. Drugs used to treat hypertension
prof. Ján Mojžiš
Department of Pharmacology,
Medical Faculty, P.J. Šafarik University
Košice

2. Target-Organ Damage Brain: stroke, transient ischemic attack, dementia
Eyes: retinopathy
Heart: left ventricular hypertrophy, angina
Kidney: chronic kidney disease
Peripheral Vasculature: peripheral arterial disease 2

3. Adult Classification < 120 < 80 Classification
Systolic BP (mmHg)
Diastolic BP (mmHg)
Normal
< 120
and
< 80
Prehypertension or
80-89
Stage 1 hypertension
90-99
Stage 2 hypertension
> 160
> 100
Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252. 3 3

4. Treatment Goals Patient Population Target BP Most patients
Reduce morbidity & mortality
Select drug therapy based on evidence demonstrating risk reduction
Patient Population
Target BP
Most patients
< 140/90 mmHg
Diabetes mellitus
< 130/80 mmHg
Chronic kidney disease
<130/80 mmHg 4

5. Hypertension Essential (primary) Secondary
- most (90-95 %) patients with persistent arterial hypertension
genesis of hypertension unknown
predisposing factors:
Secondary
is secondary to some
distinct diseases:
Renal + renovascular desease
(artery stenosis)
Hormonal defects
(Cushing´s syndrome,
pheochromocytoma)
Mechanical defect
(coarctation of aorta)
Hypertension in pregnancy
Drug-induced hypertension
(sympatomimetics,
glucocorticoids)
Neurologic disease
susceptive
(obesity, stress, salt intake, lack of Mg2+, K+, Ca2+, ethanol  dose, smoking)
non-susceptive
(positive family history, insulin resistance, age, sex, defect of local vasomotoric regualtion)

6. Treatment of hyperternsion
A: Non-pharmacological
Changes of lifestyl

7. Lifestyle Modifications
Recommendation
Systolic BP Reduction
(mm Hg)
Weight loss
Maintain normal body weight (body mass index 18.5–24.9 kg/m2)
5–20 per 10-kg weight loss
DASH-type dietary patterns
Consume a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat
8–14
Reduced salt intake
Reduce daily dietary sodium intake as much as possible, ideally to 65 mmol/day (1.5 g/day sodium, or 3.8 g/day sodium chloride)
2–8
Physical activity
Regular aerobic physical activity (at least 30 min/day, most days of the week)
4–9
Moderation of alcohol intake
Limit consumption to 2 drinks/day in men and 1 drink/day in women and lighter-weight persons
2–4
DASH, Dietary Approaches to Stop Hypertension. 7

8. Standard drink
A standard drink is about 142 ml or 5 oz of wine (12% alcohol). 341 mL or 12 oz of beer (5% alcohol) 43 mL or 1.5 oz of spirits (40% alcohol).

10. ACE-I, blockers of AT1 receptor 4. Calcium channel blockers
B. Pharmacological
Diuretics
-blockers
ACE-I, blockers of AT1 receptor
4. Calcium channel blockers
5. Other

11. Diuretics Thiazide Loop Potassium-sparing
chlorthalidone, hydrochlorothiazide (HCTZ), indapamide, metipamid, clopamid
Loop
bumetanide, furosemide, torsemide
Potassium-sparing
spironolactone, amiloride 11

12. DIURETICS – cont. THIAZIDES
drugs of first choice for treating patients with mild hypertension often combined with another drug in treatment of more severe hypertension
THIAZIDES
- preferable (to loop diuretics) for the treatment of uncomplicated hypertension - given by mouth as a single morning dose (to avoid nocturnal diuresis) - begin to act within 1-2 hours and work for hours - treatment should be started using a low dose

13. Lumen –
urine
Distal
convoluted
tubule
Interstitium -
blood
Thiazides

14. Mechanism of action:
lower blood pressure by reduction of blood volume and by direct vascular effect
inhibition of sodium chloride transport in the early segment of the distal convoluted tubule  natriuresis, decrease in preload and cardiac output - renal effect
slow decrease of total peripheral resistance (raised initially) during chronic treatment, suggesting an action on resistance vessels - extrarenal effects

15. Adverse effects
- metabolic and electrolyte changes
hyponatremia
hypokalemia (combine with potassium-sparing diuretics)
hypomagnesemia
hyperuricemia (most diuretics reduce urate clearance)
hyperglycemia
hypercalcemia (thiazides reduce urinary calcium ion clearance)
idiosyncratic reactions (rashes - may be photosensitiv, purpura)
lithium toxicity with concurrent administration

16. LOOP DIURETICS
- useful in hypertensive patients with moderate or severe renal impairment, or in patients with hypertensive heart failure
- relatively short-acting (diuresis occurs over the 4 hours following a dose)  used in hypertension if response to thiazides is inadequate
Mechanism of action:
- they inhibit the co-transport of Na+, K+ and 2Cl-
-  of Ca2+ and Mg2+ excretion
- they have useful pulmonary vasodilating effects (unknown mechanism)

17. Lumen –
urine
Thick ascending
limb
Interstitium -
blood
Furosemide

18. - hypokalemic metabolic alkalosis ( excretion of K+)
Adverse effects
- hypokalemic metabolic alkalosis ( excretion of K+)
- ototoxicity (dose dependent, reversible)
- hypomagnesemia
- hyperuricemia (block of uric acid tubular secretion)
- sulfonamide allergy
- risk of dehydration (> 4 L urine/ 24 h)
Important drug interaction may occurs if loop diuretic is given with Li+ (antimanic drug). Decrease of Na+ reabsorption can lead to increase of Li+ reabsorption  toxicity.

19. Potassium-sparing diuretics
act in the distal tubule and the collecting tubule to inhibit Na+ reabsorption, K+ secretion, H+ secretion
they are often used with a thiazide diuretic to spare potassium
Spironolactone
-  it is an aldosterone antagonist
- is useful in patients with high level of aldosterone
- it has low diuretic efficacy  its advantage is sparing of potassium
- it is often used with loop or thiazide diuretics

20. Potassium-sparing diuretics – cont.
Amiloride
- it has similar potassium-spring action to that of spironolactone
- its efect is independent on aldosterone concentration
- it si also frequently used with other diuretics
Adverse effects:
may cause hyperkalemia especially in combination with ACE inhibitor, angiotensin-receptor blocker or potassium supplements

21. -adrenoreceptor antagonists

22. β-Receptors Distributed throughout the body
concentrate differently in certain organs & tissues
β1 receptors:
heart, kidney
stimulation increases HR, contractility, renin release
β2 receptors:
lungs, liver, pancreas, arteriolar smooth muscle
stimulation causes bronchodilation & vasodilation
mediate insulin secretion & glycogenolysis
β3 receptors:
adipose tissue, skeletal muscle
stimulation causes lipolysis in adipose tissue
 thermogenesis in skeletal muscle

23. Mechanism of action Negative chronotropic & inotropic cardiac effects
Inhibit renin release (weak association with antihypertensive effect)
Membrane-stabilizing action on cardiac cells at high enough doses (?)
Possible mechanisms include:
b-adrenoceptors located on sympathetic nerve terminals can promote noradrenaline release, and this is prevented by b-receptor antagonists

24. -adrenoreceptor antagonists – cont.
cardio-selective:
1 blockers atenolol, metoprolol
1 blockers with ISA acebutol
cardio non-selective:
1 + 2 blockers metiprolol, propranolol, nadolol
1 + 2 blockers with ISA pindolol, bopindolol
1+2+ 1 blockers labetalol, carvedilol

25. Cardioselective β-Blockers
Greater affinity for β1 than β2 receptors
inhibit β1 receptors at low to moderate dose
higher doses block β2 receptors
Safer in patients with bronchospastic disease, peripheral arterial disease, diabetes
may exacerbate bronchospastic disease when selectivity lost at high doses
dose where selectivity lost varies from patient to patient
Generally preferred β-blockers 25

26. Nonselective β-Blockers
Inhibit β1 & β2 receptors at all doses
Can exacerbate bronchospastic disease
Additional benefits in:
essential tremor
migraine headache
thyrotoxicosis 26

27. -adrenoreceptor antagonists – cont.
Adverse effects
- bradycardia
- AV blockade
- CHF
- asthmatic attack (in patients with airway disease)
- hypoglycemia in patients with DM
- cold extremities
- CNS adverse effects - sedation, fatigue, and sleep alterations.

28. Angiotensin-converting enzyme inhibitors (ACE-I)

29. Captopril, enalapril, quinapril, lisinopril, perindopril, ramipril
Indications
- hypertension where thiazide diuretics and -blockers are contraindicated
- useful in hypertensive patients with heart failure (beneficial effect)
- diabetic nephropathy

30. ACE ACE-I Angiotensin I (inactive) Bradykinine (vasodilator)
(vasoconstrictor)
Inactive metabolites

31. Angiotensin I ANGIOTENSIN II
Effect of ACE-I
RENIN
Angiotensinogen
Angiotensin I ANGIOTENSIN II
ACE Inhibitors 
ACE

RECEPTORS
Treatment of congestive heart failure.
Angiotensin II inhibitors
Angiotensin II has different effects mediated via specific receptors. There are two types of tissue receptors for angiotensin: AT1 and AT2. Stimulation of AT1 receptors has a proliferative and vasoconstrictor effect, while stimulation of AT2 receptors has the opposite effects, that is, vasodilatory and antiproliferative. In the treatment of heart failure, specific blockade of the AT1 receptors is desirable. Drugs which create a selective and competitive block of the AT1 receptors include:losartan, valsartan, irbersartan and candersartan.
AT1
AT2
Vasoconstriction
Proliferative
Action
Vasodilatation
Antiproliferative
Action

32. ACE-I – cont.
Dilatation of arteriol  reduction of peripheral vascular resistance, blood pressure and afterload
Increase of Na+ and decrease of K+ excretion in kidney
Decrease noradrenaline release  reduction of sympathetic activity (use is not associated with reflex tachycardia)
Inhibition of aldosterone secretion contributes to the antihypertensive effects of ACE-I
Influence on the arteriolar and left ventricular remodelling that are believed to be important in the pathogenesis of human essential hypertension and post-infarction state

33. Summary of the three major effects of angiotensin II and the mechanisms that mediate them.

34. ACE-I – cont. Pharmacokinetics active when administered orally
most of ACE-Is are highly polar, eliminated in the urine, without CNS penetration
captopril, lisinopril - active per se
enalapril, quinapril - prodrugs  require metabolic activation
enalapril, quinapril and lisinopril - given once daily
captopril - administered twice daily

35. Duration of effect (hours)
ACE-I – cont.
Drug
Duration of effect (hours)
Short-act.
captopril
6-8
Medially-act.
enalapril 12
quinapril
Long-act.
perindopril 24
lisinopril
spirapril
ramipril

36. ACE-I – cont. Adverse effects well tolerated
First dose hypotension - particularly in those receiving diuretic therapy; the first dose should preferably be given at bedtime.
Dry cough - the most frequent (5-30%) symptom;
Urticaria and angioneurotic edema -  kinin concentrations  urticarial reactions and angioneurotic edema
Functional renal failure - mainly in patients with bilateral renal artery stenosis
Fetal injury - results in oligohydramnios, craniofacial malformations

37. ACE-I – cont. Hyperkalemia – monitor !!
- ACE-Is cause a modest increase in plasma potassium as a result of reduced aldosterone secretion.
- potassium accumulation may be marked, especially if the patient is consuming high-potassium diet and/or potasssium- sparing diuretics.

38. BLOCKERS OF AT1 RECEPTOR

39. losartan, valosartan, irbesartan
it competitively inhibit angiotensin II at its AT1 receptor site
Mechanisms responsible for antihypertensive effect:
inhibition of direct vasoconstrictive effect of A-II
decrease of sympathetic nerve activity
decrease of A-II-mediated aldosterone release
decrease of RAS activity in CNS
decrease of smooth muscle and cardiac hypertrophy and hyperplasia

40. Inhibition of the effects of angiotensin II
RENIN
Angiotensinogen
Angiotensin I ANGIOTENSIN II
ACE
Other paths
AT1
Receptor
Antagonists
AT II
AT II

RECEPTORS
Treatment of congestive heart failure.
Angiotensin II inhibitors
Angiotensin II has different effects mediated via specific receptors. There are two types of tissue receptors for angiotensin: AT1 and AT2. Stimulation of AT1 receptors has a proliferative and vasoconstrictor effect, while stimulation of AT2 receptors has the opposite effects, that is, vasodilatory and antiproliferative. In the treatment of heart failure, specific blockade of the AT1 receptors is desirable. Drugs which create a selective and competitive block of the AT1 receptors include:losartan, valsartan, irbersartan and candersartan.
AT1
AT2
Vasoconstriction
Proliferative
Action
Vasodilatation
Antiproliferative
Action

41. Other paths for A-II synthesis
angiotensinogen
renin
non-renin proteases
cathepsin
t-PA
angiotensin I
ACE
angiotensin II

42. Blockers of AT1 receptor – cont.
losartan
- prodrug (metabolite is 10-40x potent than losartan)
- rapid absorption, food has minor effect on the absorption, bound to albumin
valsartan
- active drug (40, 000 x greater affinity to AT-1 than AT-2)
rapid absorption, food has minor effect on the absorption, bound to albumin

43. Blockers of AT1 receptor – cont.
Clinical use in hypertension
losartan
-    aditive effect to hydrochlorthiazide (HCTZ)
-    fixed dose combination: losartan 50 mg mg HCTZ
valsartan
-   in placebo-controlled trials  80 mg decrease syst. and diastol. pressure aproximately about 7-10 mm Hg
-   equivalent to 20 mg of enalapril or 10 mg of lisinopril

44. BLOCKERS OF AT1 RECEPTOR – cont.
- these drugs lower blood pressure as the ACE inhibitors and have the advantage of much lower incidence of adverse effects resulting from accumulation of bradykinin (cough, angioneurotic oedema)
- they cause fetal renal toxicity (like that of the ACE inhibitors)
- these drugs reduce aldosterone levels and cause potassium accumulation (attainment of toxic levels - hazardous in patients with renal impairment)

45. Renin Inhibitor 1st agent FDA approved in 2007: aliskiren
Inhibits angiotensinogen to angiotensin I conversion
FDA approved as monotherapy & combination therapy with other antihypertensives
combination with other antihypertensives including amlodipine, HCTZ, ACEIs/ARBs
Does not block bradykinin breakdown
less cough than ACE Inhibitors
Adverse effects: orthostatic hypotension, hyperkalemia

46. Calcium channel blockers
(CCBs)

47. 1. dihydropyridines (nifedipine, nicardipine, amlodipine)
2. benzothiazepines (diltiazem)
3. phenylalkylamines (verapamil)
4. tetralol (mibefradil)
they block voltage-dependent „L-type“ calcium channels  relaxation of smooth muscle  vasodilation  reduce peripheral vascular resistance  reduction of BP
negatively inotropic drugs
they differ in selectivity for calcium channels in vascular smooth muscles and cardiac tissues

48. Dihydropyridine CCBs
Dihydropyridines more potent peripheral vasodilators than non-dihydropyridines
may cause more reflex sympathetic discharge: tachycardia, dizziness, headaches, flushing, peripheral edema
Additional benefits in Raynaud’s syndrome
Effective in older patients with isolated systolic hypertension 48

49. Indication: all grades of essential hypertension
alone (nifedipine, amlodipine) in patients with mild hypertension for patients in whom thiazide diuretics and b-blockers are contraindicated
combinations
angina (with -blockers)

50. Non-dihydropyridine CCBs
extended release products preferred for hypertension
Block cardiac SA (diltiazem) or AV (verapamil) nodes: reduce HR
May produce heart block
Additional benefits in patients with atrial tachyarrhythmia 50

51. Unwanted effects
reflex tachycardia if nifedipine-like drugs are used
constipation
dizziness
headache, flushing, ankle swelling
fatigue
AV block

52. Mibefradil - newest calcium blocker - blockade of L and T channels
-  do not possess the negative inotropic effect of verapamil and diltiazem
-  it can depres cardiac conductance
- it is not associated vith peripheral edema and reflex tachycardia of the dihydropyridines
- antihypertensive effect is evident within the first week of therapy
- efficacy may be diminished in dietary sodium restriction and diuretic co-therapy (both stimulate renin activity)

53. Other -adrenoreceptor antagonists centrally acting symatomimetics
direct vasodilators

54. -adrenoreceptor antagonists
Mechanism of action:
- vasodilatation (reduce vascular resistence) and decreased blood pressure by antagonizing of tonic action of noradrenaline on a1 receptors (vascular smooth muscle)
nonselective
a. short-term action:
phentolamine
b: long-term action
phenoxybenzamine
selective
prazosin, uradipil
b. long-acting
doxazosin, terazosin

55. -adrenoreceptor antagonists – cont.
Adverse reaction
- the main manifestations are:
- drowsiness, weakness, orthostatic hypotension (first dose – bedtime administration)
- for the nonselective agents, tachycardia - in patients with coronary disease, angina may be precipitated by the tachycardia
- oral administration of any of these drugs can cause nausea, vomiting, diarrhoea
- urinary incontinence
- priapism, nasal congestion

56. Centrally acting drugs
a2-agonists
Clonidine, Moxonidine
direct a2-agonist, imidazol receptor agonists (I1)
Methyldopa
false neurotransmitter  corbadrine (a2-agonist)
- limited use in the treatment of hypertension.
- methyldopa  hypertension during pregnancy
- methyldopa causes symptoms of drowsiness and fatigue that are intolerable to many adult patients in long-term use
- they are seldom used to treat essential hypertension
- clonidine is potent but poorly tolerated (rebound hypertension, if it is discontinued abruptly, is an uncommon but severe problem)

57. Centrally acting drugs – cont.
Adverse effects
- drowsiness, fatigue (esp. methyldopa), depression, nightmares
- nasal congestion, anticholinergic symptoms (constipation, bradycardia) – clonidine
- dry mouth
- hepatitis, drug fever (methyldopa)
- sexual dysfunction, salt and water retention
- hypertensive rebound associated with anxiety, sweating, tachycardia and extrasystoles (rarely hypertensive crisis)

58. Direct Arterial Vasodilators
Direct arterial smooth muscle relaxation causes antihypertensive effect (little or no venous vasodilation)
reduce impedence to myocardial contractility
potent reductions in perfusion pressure activate baroreceptor reflexes
baroreceptor activation: compensatory increase in sympathetic outflow; tachyphylaxis can cause loss of antihypertensive effect
counteract with concurrent β-blocker
clonidine if β-blocker contraindicated 58

59. Vasodilators – cont. * opening of potassium channels
drugs which dilate blood vessels (and decrease peripheral vascular resistance) by acting on smooth muscle cells through non-autonomic mechanisms:
* release of nitric oxide
* opening of potassium channels

60. Drugs acting via NO release
Sodium nitroprusside
short-acting agent (few minutes)  administrated by infusion in hypertensive emergencies (hypertensive encephalopathy, shock, cardiac dysfunction) for max 24 hours (risk of cyanide cummulation  toxicity)
photodeactivation
- adverse effects: too rapid reduction of BP, nausea, palpitation, dizziness

61. Openers of potassium channels
Minoxidil, diazoxide, nicorandil, pinacidil, cromakalim
Minoxidil
- therapy of severe hypertension resistant to other drugs
- prodrug  its metabolite (minoxidil sulfate) is a potassium channel opener ( repolarization + relaxation of vascular smooth muscle)
- more effect on arterioles than on veins
orally active
- Adverse effects: Na+ and water retention → coadministration with -blocker and diuretic, oedemas, hypertrichosis, breast tenderness

62. Openers of potassium channels – cont.
Diazoxide
given by rapid iv. injection (less than 30 seconds) in hypertensive emergencies
glucose intolerance  due to reduced insulin secretion (used in patients with inoperable insulinoma)
- adverse effects: Na+ and water retention, hyperglycaemia, hirsutism

63. Possible combinations of antihypertensives
Thiazides
β-blockers
AT1 RB
α- blockers
CCB
ACE-I
The most rationale combinations 63

64. INITIAL TREATMENT AND MONOTHERAPY Lifestyle modification
Treatment of Adults with Systolic/Diastolic Hypertension without Other Compelling Indications
TARGET <140/90 mmHg
INITIAL TREATMENT AND MONOTHERAPY
Lifestyle modification
therapy
Thiazide
ACE-I
ARB
Long-acting
CCB
Beta- blocker*
* BBs are not indicated as first line therapy for age 60 and above
ACEI and ARB are contraindicated in pregnancy and caution is required in prescribing to women of child bearing potential

65. Threshold equal or over 130/80 mmHg and TARGET below 130/80 mmHg
Treatment of Hypertension in association with Diabetes Mellitus: Summary
Threshold equal or over 130/80 mmHg and TARGET below 130/80 mmHg
Diabetes
with
Nephropathy
Combination
(Effective
2-drug combination)
ACE Inhibitor
or ARB
without
1. ACE-Inhibitor or ARB or
2. Thiazide diuretic or DHP-CCB
3. For persons with diabetes and normal urinary albumin excretion (less than 30 mg/day) and blood pressure greater than 130/80 mm Hg despite lifestyle interventions, an ACE inhibitor (Grade A for persons aged greater than or equal to 55 years, Grade B for persons aged less than 55 years), or an angiotensin II receptor blocker (Grade A for persons with LVH and age greater than or equal to 55 years, Grade B for persons without LVH irrespective of age) or a thiazide diuretic (Grade A for persons aged greater than or equal to 55 years, Grade B for persons aged less than 55 years) is recommended. If these drugs are contraindicated or cannot be tolerated, a cardioselective beta-adrenergic blocker (grade B) or long acting calcium channel blocker (grade C) can be substituted. If blood pressure targets cannot be reached despite an ACE inhibitor, angiotensin II receptor blocker, or thiazide diuretic, then these drugs in combination or addition of one or more of a cardioselective beta-blocker or long acting calcium channel blocker can be considered (Grade D).
Comment: The recommendation of the use of a thiazide diuretic as first-line therapy in hypertensive patients with diabetes and normal urinary albumin excretion (along with ACE-inhibitors and ARBs) is based on interpretation of the results from ALLHAT.
4. For persons with diabetes and a serum creatinine over 150 mol/L, the choice of antihypertensive drugs is the same as above, except that a loop diuretic should be substituted for a thiazide diuretic if control of volume is desired (grade D).
Comment: Note that the implicit restriction of the use of thiazides to a “low dose” has been removed. This is based on the observation that the ALLHAT chlorthalidone regimen could not be viewed as a “low-dose” regimen.
More than 3 drugs may be needed to reach target values for diabetic patients
If Creatinine over 150 µmol/L or creatinine clearance below 30 ml/min ( 0.5 ml/sec), a loop diuretic should be substituted for a thiazide diuretic if control of volume is desired

66. Chronic kidney disease and proteinuria * Combination with other agents
Treatment of Hypertension in Patients with Non Diabetic Chronic Kidney Disease
Target BP: Nondiabetic: < 130/80 mmHg
Chronic kidney disease and proteinuria *
1. ACE-I
2. Alternate if ACE-I not tolerated: ARB
Additive therapy: Thiazide diuretic.
Alternate: If volume overload: loop diuretic
Combination with other agents
* albumin:creatinine ratio [ACR] > 30 mg/mmol
or urinary protein > 500 mg/24hr

67. Thiazides — particularly indicated for hypertension in the elderly; a contra-indication is gout;
-blockers — indications include myocardial infarction, angina; compelling contra-indications include asthma, heart block;
ACE inhibitors — indications include heart failure, left ventricular dysfunction and diabetic nephropathy; contra-indications include renovascular disease and pregnancy; when thiazides and beta-blockers are contra-indicated, not tolerated, or fail to control blood pressure
Angiotensin-II receptor antagonists are alternatives for those who cannot tolerate ACE inhibitors because of persistent dry cough, but they have the same contra-indications as ACE inhibitors;
Calcium-channel blockers. a) Dihydropyridine calcium-channel blockers are valuable in isolated systolic hypertension in the elderly when a low-dose thiazide is contra-indicated or not tolerated. b) ‘Rate-limiting’ calcium-channel blockers (e.g. diltiazem, verapamil) may be valuable in angina; contra-indications include heart failure and heart block;
-blockers — a possible indication is prostatism; a contra-indication is urinary incontinence.

68. Hypertensive Emergency
Drug
Dose
Onset (min)
Duration (min)
Adverse Effects
Special Indications
Sodium nitroprusside
0.25–10 mcg/kg/min intravenous infusion
Immediate
1–2
Nausea, vomiting, muscle twitching, sweating, thiocyanate and cyanide intoxication
Most hypertensive emergencies; caution with high intracranial pressure, azotemia, or in chronic kidney disease
Nicardipine hydrochloride
5–15 mg/h intravenous
5–10
15–30;
may exceed 240
Tachycardia, headache, flushing, local phlebitis
Most hypertensive emergencies except acute heart failure; caution with coronary ischemia
Clevidipine butyrate
1-2 mg/h intravenous infusion; may double dose every 90 sec initially; maximum: 32 mg/h; typical maintenance dose: 4 to 6 mg/h
2-4
5-15
Headache, syncope, dyspnea, nausea, vomiting
Most hypertensive emergencies except severe aortic stenosis; caution with heart failure
Fenoldopam mesylate
0.1–0.3 mcg/kg/min intravenous infusion
< 5 30
Tachycardia, headache, nausea, flushing
Most hypertensive emergencies; caution with glaucoma

69. Hypertensive Emergency
Drug
Dose
Onset (min)
Duration (min)
Adverse Effects
Special Indications
Nitroglycerin
5–100 mcg/min intravenous infusion
2–5
5–10
Headache, vomiting, methemoglobinemia, tolerance with prolonged use
Coronary ischemia
Hydralazine hydrochloride
12–20 mg intravenous
10–50 mg intramuscular
10–20
20–30
60–240
240–360
Tachycardia, flushing, headache vomiting, aggravation of angina
Eclampsia
Labetalol hydrochloride
20–80 mg intravenous bolus every 10 min; 0.5–2.0 mg/min intravenous infusion
180–360
Vomiting, scalp tingling, bronchoconstriction, dizziness, nausea, heart block, orthostatic hypotension
Most hypertensive emergencies except acute heart failure
Esmolol hydrochloride
250–500 mcg/kg/min intravenous bolus, then 50–100 mcg/kg/min intravenous infusion; may repeat bolus after 5 min or increase infusion to 300 mcg/min
1–2
Hypotension, nausea, asthma, first-degree heart block, heart failure
Aortic dissection; perioperative
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: 69