drugs used to treat hypertension n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Drugs used to treat hypertension PowerPoint Presentation
Download Presentation
Drugs used to treat hypertension

Loading in 2 Seconds...

play fullscreen
1 / 69

Drugs used to treat hypertension - PowerPoint PPT Presentation


  • 172 Views
  • Uploaded on

Drugs used to treat hypertension. prof. Ján Mojžiš Department of Pharmacology, Medical Faculty, P.J. Šafarik University Košice. Target-Organ Damage. Brain : stroke, transient ischemic attack, dementia Eyes : retinopathy Heart : left ventricular hypertrophy, angina

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Drugs used to treat hypertension' - shiri


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
drugs used to treat hypertension

Drugs used to treat hypertension

prof. Ján Mojžiš

Department of Pharmacology,

Medical Faculty, P.J. Šafarik University

Košice

target organ damage
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

adult classification
Adult Classification

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

treatment goals
Treatment Goals

Reduce morbidity & mortality

Select drug therapy based on evidence demonstrating risk reduction

4

slide5

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 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)

treatment of hyperternsion
Treatment of hyperternsion

A: Non-pharmacological

Changes of lifestyl

lifestyle modifications
Lifestyle Modifications

7

DASH, Dietary Approaches to Stop Hypertension.

standard drink
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).

slide10

B. Pharmacological

  • Diuretics
  • -blockers
  • ACE-I, blockers of AT1 receptor
  • 4. Calcium channel blockers
  • 5. Other
diuretics
Diuretics
  • Thiazide
    • chlorthalidone, hydrochlorothiazide (HCTZ), indapamide, metipamid, clopamid
  • Loop
    • bumetanide, furosemide, torsemide
  • Potassium-sparing
    • spironolactone, amiloride

11

slide12

DIURETICS – cont.

- 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

  • drugs of first choice for treating patients with mild hypertension often combined with another drug in treatment of more severe hypertension

THIAZIDES

slide13

Lumen –

urine

Distal

convoluted

tubule

Interstitium -

blood

Thiazides

slide14

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 cardiacoutput -renal effect
  • slow decrease of total peripheral resistance(raised initially) during chronic treatment, suggesting an action on resistance vessels -extrarenal effects
slide15

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
slide16

LOOP DIURETICS

- useful in hypertensive patients with moderate or severe renalimpairment, 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)

slide17

Lumen –

urine

Thick ascending

limb

Interstitium -

blood

Furosemide

slide18

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.

potassium sparing diuretics
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

potassium sparing diuretics cont
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
receptors
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 adiposetissue
    •  thermogenesis in skeletal muscle
slide23

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
slide24

-adrenoreceptor antagonists– cont.

cardio-selective:

1 blockersatenolol, metoprolol

1 blockers with ISA acebutol

cardio non-selective:

1 + 2 blockersmetiprolol, propranolol, nadolol

1 + 2 blockers with ISApindolol, bopindolol

1+2+ 1 blockerslabetalol, carvedilol

cardioselective blockers
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

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

26

slide27

-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.

slide29

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

slide30

Angiotensin I

(inactive)

Bradykinine

(vasodilator)

ACE

ACE-I

Angiotensin II

(vasoconstrictor)

Inactive metabolites

effect of ace i
Effect of ACE-I

RENIN

ACE Inhibitors

Angiotensin IANGIOTENSIN II

Angiotensinogen

ACE



RECEPTORS

AT1

AT2

Vasoconstriction

Proliferative

Action

Vasodilatation

Antiproliferative

Action

slide32

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

Decreasenoradrenaline release  reduction of sympatheticactivity (use is not associated with reflex tachycardia)

Inhibition of aldosteronesecretion contributes to the antihypertensive effects of ACE-I

Influence on the arteriolar and left ventricularremodellingthat are believed to be important in the pathogenesis of human essential hypertension and post-infarction state

slide34

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
slide36

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 renalartery stenosis
  • Fetal injury- results in oligohydramnios, craniofacial malformations
slide37

ACE-I – cont.

Hyperkalemia – monitor !!

- ACE-Is cause a modest increase in plasma potassium as aresult of reduced aldosterone secretion.

- potassium accumulation may be marked, especially if thepatient is consuming high-potassium diet and/or potasssium-sparing diuretics.

slide39

losartan, valosartan, irbesartan

  • itcompetitively inhibit angiotensin IIat 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
inhibition of the e ffects of a ngiotensin ii
Inhibition of the effects of angiotensin II

RENIN

Angiotensin IANGIOTENSIN II

Angiotensinogen

ACE

Other paths

AT1

Receptor

Antagonists

AT II

AT II



RECEPTORS

AT1

AT2

Vasoconstriction

Proliferative

Action

Vasodilatation

Antiproliferative

Action

slide41

Other paths for A-II synthesis

angiotensinogen

renin

non-renin proteases

cathepsin

t-PA

angiotensin I

ACE

angiotensin II

blockers of at1 receptor cont
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

blockers of at1 receptor cont1
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

slide44

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 patientswith renal impairment)

renin inhibitor
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
slide47

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
dihydropyridine ccbs
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

slide49
Indication: all grades of essential hypertension
  • alone (nifedipine, amlodipine) in patients with mild hypertensionfor patients in whom thiazide diuretics and b-blockers are contraindicated
  • combinations
  • angina (with -blockers)
non dihydropyridine ccbs
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

slide51

Unwanted effects

  • reflex tachycardia if nifedipine-like drugs are used
  • constipation
  • dizziness
  • headache, flushing, ankle swelling
  • fatigue
  • AV block
m ibefradil
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)

other
Other
  • -adrenoreceptor antagonists
  • centrally acting symatomimetics
  • direct vasodilators
slide54

-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

a.short-term action:

prazosin, uradipil

b. long-acting

doxazosin, terazosin

slide55

-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 beprecipitated by the tachycardia

- oral administration of any of these drugs can causenausea, vomiting, diarrhoea

- urinary incontinence

- priapism, nasal congestion

slide56

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 isdiscontinued abruptly, is an uncommon but severe problem)

slide57

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)

direct arterial vasodilators
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

slide59

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
slide60

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
slide61

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 channelopener ( 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

slide62

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 inoperableinsulinoma)
  • - adverse effects:Na+ and water retention, hyperglycaemia, hirsutism
possible combinations of antihypertensives
Possible combinations of antihypertensives

Thiazides

AT1 RB

β-blockers

CCB

α- blockers

ACE-I

The most rationale combinations

treatment of adults with systolic diastolic hypertension without other compelling indications

ARB

ACE-I

Treatment of Adults with Systolic/Diastolic Hypertension without Other Compelling Indications

TARGET <140/90 mmHg

INITIAL TREATMENT AND MONOTHERAPY

Lifestyle modification

therapy

Thiazide

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

treatment of hypertension in association with diabetes mellitus summary

ACE Inhibitor

or ARB

with

Nephropathy

Diabetes

1. ACE-Inhibitor or ARB

or

2. Thiazide diuretic or DHP-CCB

Combination

(Effective

2-drug combination)

without

Nephropathy

Treatment of Hypertension in association with Diabetes Mellitus: Summary

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

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

treatment of hypertension in patients with non diabetic chronic kidney disease
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

slide67

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.

hypertensive emergency1
Hypertensive Emergency

69

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