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prof. Ján MojžišDepartment of Pharmacology,

Medical Faculty, P.J. Šafarik UniversityKošice

Drugs used to treat hypertension

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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

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Adult Classification

ClassificationSystolic BP

(mmHg)Diastolic BP

(mmHg)

Normal < 120 and < 80

Prehypertension 120-139 or 80-89

Stage 1 hypertension

140-159 or 90-99

Stage 2 hypertension

> 160 or > 100

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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.

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Treatment Goals

• Reduce morbidity & mortality • Select drug therapy based on evidence

demonstrating risk reduction

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Patient Population Target BP

Most patients < 140/90 mmHg

Diabetes mellitus < 130/80 mmHg

Chronic kidney disease <130/80 mmHg

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Hypertension

Essential (primary)- 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 pregnancyDrug-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)

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Treatment of hyperternsion

A: Non-pharmacological

Changes of lifestyl

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Lifestyle Modifications

Modification RecommendationSystolic 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

7DASH, Dietary Approaches to Stop Hypertension.

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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).

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B. Pharmacological

1. Diuretics

2. -blockers

3. ACE-I, blockers of AT1 receptor

4. Calcium channel blockers

5. Other

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Diuretics

• Thiazide –chlorthalidone, hydrochlorothiazide (HCTZ),

indapamide, metipamid, clopamid

• Loop–bumetanide, furosemide, torsemide

• Potassium-sparing–spironolactone, amiloride

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DIURETICS – cont.

- 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 12-24 hours

- treatment should be started using a low dose

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Thiazides

Lumen –urine

Distal convoluted

tubule

Interstitium - blood

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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

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- 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

Adverse effects

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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)

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Lumen –urine

Thick ascending limb

Furosemide

Interstitium - blood

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- 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.

Adverse effects

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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

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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

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-adrenoreceptor antagonists

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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

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- 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: -adrenoceptors located on sympathetic nerve terminals can promote noradrenaline release, and this is prevented by -receptor antagonists

Mechanism of action

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cardio-selective:

1 blockers atenolol, metoprolol

1 blockers with ISAacebutol

cardio non-selective:

1 + 2 blockers metiprolol, propranolol, nadolol

1 + 2 blockers with ISA pindolol, bopindolol

1+2+ 1 blockers labetalol, carvedilol

-adrenoreceptor antagonists – cont.

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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

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Nonselective β-Blockers

• Inhibit β1 & β2 receptors at all doses

• Can exacerbate bronchospastic disease

• Additional benefits in:– essential tremor– migraine headache– thyrotoxicosis

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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.

-adrenoreceptor antagonists – cont.

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Angiotensin-converting enzyme inhibitors (ACE-I)

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- hypertension where thiazide diuretics and -blockers

are contraindicated

- useful in hypertensive patients with heart failure

(beneficial effect)

- diabetic nephropathy

Captopril, enalapril, quinapril, lisinopril, perindopril, ramipril

Indications

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ACE

Angiotensin I(inactive)

Angiotensin II(vasoconstrictor)

Bradykinine(vasodilator)

Inactive metabolites

ACE-I

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RENIN

Angiotensinogen Angiotensin I

ANGIOTENSIN II

ACE

Vasoconstriction Proliferative Action

Vasodilatation Antiproliferative Action

AT1 AT2RECEPTORS

ACE Inhibitors

Effect of ACE-I

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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

Dilatation of arteriol reduction of peripheral vascular resistance, blood pressure and afterload

Increase of Na+ and decrease of K+ excretion in kidney

ACE-I – cont.

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

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Pharmacokinetics

- active when administered orally- most of ACE-Is are highly polar, eliminated in the urine, without CNS penetration

captopril, lisinopril - active per seenalapril, quinapril - prodrugs require metabolic activation

enalapril, quinapril and lisinopril - given once dailycaptopril - administered twice daily

ACE-I – cont.

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Drug Duration of effect (hours)

Short-act. captopril 6-8Medially-act. enalapril 12

quinapril

Long-act.

perindopril

24lisinopril

spirapril

ramipril

ACE-I – cont.

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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

ACE-I – cont.

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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.

ACE-I – cont.

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BLOCKERS OF AT1 RECEPTOR

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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

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RENIN

Angiotensinogen Angiotensin I

ANGIOTENSIN II

ACEOther paths

Vasoconstriction Proliferative Action

Vasodilatation Antiproliferative Action

AT1 AT2

AT1 Receptor

AntagonistsRECEPTORS

Inhibition of the effects of angiotensin II

AT II AT II

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angiotensinogen

angiotensin I

angiotensin II

renin

ACE

non-renin proteasescathepsin

t-PA

Other paths for A-II synthesis

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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

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Blockers of AT1 receptor – cont.

Clinical use in hypertension

 

losartan

-    aditive effect to hydrochlorthiazide (HCTZ)

-    fixed dose combination: losartan 50 mg + 12.5 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

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- 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)

BLOCKERS OF AT1 RECEPTOR – cont.

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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

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Calcium channel blockers

(CCBs)

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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

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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

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• 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)

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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

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Unwanted effects

- reflex tachycardia if nifedipine-like drugs are used

- constipation

- dizziness

- headache, flushing, ankle swelling

- fatigue

- AV block

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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)

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Other

)-adrenoreceptor antagonists

b)centrally acting symatomimetics

c)direct vasodilators

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Mechanism of action:

- vasodilatation (reduce vascular resistence) and decreased blood pressure by antagonizing of tonic action of noradrenaline on 1 receptors (vascular smooth muscle)

nonselective a. short-term action:

phentolamineb: long-term action

phenoxybenzamineselective

a. short-term action:prazosin, uradipil

b. long-acting doxazosin, terazosin

-adrenoreceptor antagonists

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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

-adrenoreceptor antagonists – cont.

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2-agonists

Clonidine, Moxonidine

direct 2-agonist, imidazol receptor agonists (I1)

Methyldopa

false neurotransmitter corbadrine (2-agonist)

Centrally acting drugs

- 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)

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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)

Centrally acting drugs – cont.

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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

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Vasodilators – cont.

- 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

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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

Drugs acting via NO release

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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

Openers of potassium channels

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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

Openers of potassium channels – cont.

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Possible combinations of antihypertensives

Thiazides

ACE-I

β-blockers AT1 RB

CCBα- blockers

The most rationale combinations

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Treatment of Adults with Systolic/Diastolic Hypertension

without Other Compelling IndicationsTARGET <140/90 mmHg

INITIAL TREATMENT AND MONOTHERAPY

* BBs are not indicated as first line therapy for age 60 and above

Beta-blocker*

Long-actingCCB

Thiazide ACE-I ARB

Lifestyle modificationtherapy

ACEI and ARB are contraindicated in pregnancy and caution is required in prescribing to women of child bearing potential

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Treatment of Hypertension in association with Diabetes Mellitus: Summary

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

Threshold equal or over 130/80 mmHg and TARGET below 130/80 mmHg

Diabetes

withNephropathy

Combination(Effective

2-drug combination)

ACE Inhibitoror ARB

withoutNephropathy

1. ACE-Inhibitor or ARB

or

2. Thiazide diuretic or DHP-CCB

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Treatment of Hypertension in Patients with Non Diabetic Chronic Kidney Disease

Target BP: Nondiabetic: < 130/80 mmHg

Chronic kidney disease and proteinuria *

1. ACE-I2. Alternate if ACE-I not tolerated: ARB

Combination with other agents

Additive therapy: Thiazide diuretic.Alternate: If volume overload: loop diuretic

* albumin:creatinine ratio [ACR] > 30 mg/mmol or urinary protein > 500 mg/24hr

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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.

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Hypertensive EmergencyDrug 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

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Hypertensive EmergencyDrug Dose Onset

(min)Duration

(min)Adverse Effects Special

IndicationsNitroglycerin 5–100 mcg/min

intravenous infusion2–5 5–10 Headache, vomiting,

methemoglobinemia, tolerance with prolonged use

Coronary ischemia

Hydralazine hydrochloride

12–20 mg intravenous10–50 mg intramuscular

10–2020–30

60–240240–360

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

5–10 180–360 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 10–20 Hypotension, nausea, asthma, first-degree heart block, heart failure

Aortic dissection; perioperative

69DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/