Treatment of Hypertension: 7 classification

CategoriesBP Systolic DiastolicNormal >120 <80

Prehypertension 120-139 80-89

Stage1 149-159 90-99

Stage2 >160 >100

Risk factors1. Age above 55 and 65 in Men and

Woman respectively2. Family History3. Smoking4. DM and Dyslipidemia5. Hypertension6. Obesity7. Microalbuminuria

Treatment of Hypertension –

7 compelling Indications: Heart failure Coronary artery disease H/o MI H/o stroke Diabetes Chronic Renal failure

Treatment of Hypertension

Treatment of Hypertension – General principles

Stage I: Start with a single most appropriate drug with a low dose. Preferably start

with Thiazides. Others like beta-blockers, CCBs, ARBs and ACE inhibitors may also be considered. CCB – in case of elderly and stroke prevention. If required increase the dose moderately

Partial response or no response – add from another group of drug, but remember it should be a low dose combination

If not controlled – change to another low dose combination In case of side effects lower the dose or substitute with other group

Stage 2: Start with 2 drug combination – one should be diuretic

Treatment of Hypertension – combination therapy

In clinical practice a large number of patients require combination therapy – the combination should be rational and from different patterns of haemodynamic effects Sympathetic inhibitors (not beta-blockers) and vasodilators + diuretics Diuretics, CCBs, ACE inhibitors and vasodilators + beta blockers (blocks

renin release) Hydralazine and CCBs + beta-blockers (tachycardia countered) ACE inhibitors + diuretics

3 (three) Drug combinations: CCB+ACE/ARB+diuretic; CCB+Beta blocker+ diuretic; ACEI/ARB+ beta blocker+diuretic

Treatment of Hypertension.

Never combine: Alpha or beta blocker and clonidine - antagonism Nifedepine and diuretic synergism Hydralazine with DHP or prazosin – same type of action Diltiazem and verapamil with beta blocker – bradycardia Methyldopa and clonidine

Hypertension and pregnancy: No drug is safe in pregnancy Avoid diuretics, propranolol, ACE inhibitors, Sodium nitroprusside etc Safer drugs: Hydralazine, Methyldopa, cardioselective beta blockers and

prazosin

Treatment guidelines (ESH/ESC 2007)

Average risk Low added risk Moderate added risk High added risk Very high added riskESH – ESC Guidelines Committee. J Hypertens 2007; 25: 1105–1187

Complications of Hypertension:End-Organ Damage

Chobanian AV, et al. JAMA. 2003;289:2560-2572.

Peripheral Vascular Disease Renal Failure,

Proteinuria

LVH, CHD, CHFHemorrhage,Stroke

Retinopathy

CHD = coronary heart diseaseCHF = congestive heart failureLVH = left ventricular hypertrophy

Hypertension

Conditions favouring the use of some antihypertensive drugs versus other• Subclinical organ damage:

LVH ACEI, CA, ARB

Asymptomatic Atherosclerosis CA, ACEI

Microalbuminuria ACEI, ARB

Renal dysfunction ACEI, ARB

Conditions favouring the use of some antihypertensive drugs versus other• Clinical event: Previous stroke any BP lowering agent Previous MI BB, ACEI, ARB Heart failure diuretics, BB, ACEI, ARB, anti-aldosterone agents Tachyarrhythmias BB Periph.art.disease CA LV dysfunction ACEI

Conditions favouring the use of some antihypertensive drugs versus other• Condition : ISH (elderly) diuretics,CA Metabolic syndrome ACEI,ARB,CA Diabetes mellitus ACEI, ARB Pregnancy CA,methyldopa,BB Glaucoma BB

Monotherapy versus combination therapy

• Monotherapy allows to achieve BP target only in a limited number of patients

• Use of more than one agent is necessary to achieve target BP

• Initial therapy: monotherapy or combination of two drugs in low doses with subsequent increase in drug doses or number

Monotherapy versus combination therapy

• Monotherapy in mild BP elevation with low or moderate total CV risk• Two drugs at low doses should be preferred as the first step when BP

is in grade 2 or 3 or total CV risk is high or very high with mild hypertension

• Fixed combination of two drugs simplify the treatment• If BP control is not achieved by two drugs, combination of three or

more drugs is required

Possible combinations of different classes of antihypertensive agents

The preferred combinations in general hypertensive population are represented as thick lines. The frames indicate classes of agents proven to be beneficial

in controlled interventional trials

Diuretics

AT1-receptorblockers

β-blockers

α-blockers CCBs

ACE inhibitorsACE, angiotensin-converting enzymeAT, angiotensinCCB, calcium-channel blocker

ESH – ESC Guidelines Committee. J Hypertens 2007; 25: 1105–1187

Antihypertensive therapy in special groups

• Elderly patients• Diabetic patients• Patients with renal dysfunction• Patients with cerebrovascular disease• Patients with coronary heart disease and heart failure• Patients with atrial fibrillation

Beta-adrenergic blockers Non selective: Propranolol (others: nadolol, timolol, pindolol, labetolol) Cardioselective: Metoprolol (others: atenolol, esmolol, betaxolol)

All beta-blockers similar antihypertensive effects – irrespective of additional properties

Reduction in CO but no change in BP initially but slowly Adaptation by resistance vessels to chronically reduced CO – antihypertensive action Other mechanisms – decreased renin release from kidney (beta-1 mediated) Reduced NA release and central sympathetic outflow reduction Non-selective ones – reduction in g.f.r but not with selective ones Drugs with intrinsic sympathomimetic activity may cause less reduction in HR and CO  

Beta-adrenergic blockers Advantages:

No postural hypotension No salt and water retention Low incidence of side effects Low cost Once a day regime Preferred in young non-obese patients, prevention of sudden cardiac death in post

infarction patients and progression of CHF Drawbacks (side effects):

Fatigue, lethargy (low CO?) – decreased work capacity Loss of libido – impotence Cognitive defects – forgetfulness Difficult to stop suddenly Therefore cardio-selective drugs are preferred now

Beta-adrenergic blockers Advantages of cardio-selective over non-selective:

In asthma In diabetes mellitus In peripheral vascular disease

Current status: JNC 7 recommends - 1st line of antihypertensive along with diuretics and

ACEIs Preferred in young non-obese hypertensive Angina pectoris and post angina patients Post MI patients – useful in preventing mortality In old persons, carvedilol – vasodilatory action can be given

The End

Adrenergic ReceptorsReview of ANS

Sympathetic Nervous System Alpha 1 = vasoconstriction Alpha 2 = feedback/vasodilation Beta 1 = increases heart rate Beta 2 = bronchodilation

Beta Adrenergic Blocking Agents Known as Beta-blockers Axn: Inhibit cardiac response to sympathetic

nerve stimulation by blocking Beta receptors Decreases heart rate and C.O. Decreases blood pressure

Beta Adrenergic Blocking Agents Examples – “olol” names

Beta 1: Atenolol Beta 1 and 2: Propranolol

Nursing Implications

Can not be abruptly discontinued Check baseline b.p. Check hx. of resp. condition-aggravates

bronchoconstriction

Side effects

Bradycardia Bronchospasm, wheezing Diabetic: hypoglycemia Heart failure: edema,dyspnea,rhales

DIURETICS

• MOA:• 1- ↑ renal excretion of Na & water ↓ plasma volume ↓ C.O. • 2- ↓ peripheral resistance ( desensitize smooth muscles

to action of catecholamines )

1-Thiazide

• Sulfonamide molecule• Prolonged action• Flat curve response• Potentiates action of other anti HTN• Eg: Hydrochlorothiazide ( Ezidrex ) , Bendrofluazide • SE: hypo K+ , hypo Na+, hyperuricemia, hyperglycemia,

lipid profile disturb.

2 -Loop Diuretics

• Steep curve response• Restricted to CCF & CRF• Eg: Frusemide • SE: ↓ K+ , ↓ Na+ , hypotension, ototoxic in v.high doses

3 -K+ sparing diuretics

• Not effective alone, so used in combination• Eg: Spironolactone, Amiloride , Uniretic ( HCT + Amiloride)• SE: ↑ K+, gynecomastia

Beta Blockers

• MOA:• Block beta receptors ↓ sympathetic drive • 1- ↓ H.R. & contractility, ↑ P.R. ↓ C.O.• 2- ↓ Renin release & activity ↓ Ang II ↓BPAct as anti HTN within 3-7 days

Beta Blockers• Metabolism: Hydroxylated in liver to water soluble compounds

excreted in kidneys

• Preferred in HTN with angina, SVT, HOCM, Thyrotoxicosis, Pheochromocytoma, Migraine and L.cirrhosis.

Beta Blockers• SE: bradycardia, bronchospasm, cold extremeties,

hypoglycemia, insomnia, bad dreams• Overdose: hypotension, bradycardia, bronchospasm,

coma ( treated with Atropine, Isoprenaline, glucagon )• C.I: HF, Asthma, DM, H.Block, Periph.vascular diseases ,

Hyperlipidemia

Beta Blockers• Atenolol: less lipid soluble less CNS SE• Timolol: lipid soluble more CNS SE.

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

compensatory responses to pressor agents including angiotensin II and noradrenaline are reduced during chronic treatment with thiazides- used with loop diuretic - synergistic effect occurs

Thiazides

Adverse effects:- Idiosyncratic reactions (rashes - may be photosensitiv, purpura)- Increased plasma renin (which limits the magnitude of their effect on BP)- Metabolic and electrolyte changes

HyponatremiaHypokalemia

(combine with potassium-sparing diuretics)HypomagnesemiaHyperuricemia (most diuretics reduce urate clearance)Hyperglycemia Hypercalcemia

(thiazides reduce urinary calcium ion clearance precipitate clinically significant hypercalcemia in hypertensive patients withhyperparathyroidism)

Hypercholesterolemia (a small in plasma cholesterol concentration)

Thiazides

LOOP DIURETICS furosemid

- 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 Cl-

- of Ca2+ and Mg2+ excretion - they have useful pulmonary vasodilating effects (unknown mechanism)

Toxicity:- hypokalemic metabolic alkalosis (increased excretion of K+)- ototoxicity (dose dependent, reversible) - decrease of Mg2+ plasma concentration (hypomagnesemia)- hyperuricemia (competition with uric acid about tubular secretion)- sulfonamide allergy - risk of dehydration (> 4 L urine/ 24 h)

Imporatant drug interaction may occurs if loop diuretic is given with Li+ (thymoprofylactic drug). Decrease of Na+ reabsorption can lead to increase of Li+ reabsorption toxicity.

LOOP DIURETICS

b -adrenoreceptor antagonistsMechanism of action:

- the fall in cardiac output BP- they reduce renin secretion- CNS-effects ???- additional mechanisms involve baroreceptors or other homeostatic adaptations

Possible mechanisms include: b-adrenoceptors located on sympathetic nerve terminals can promote noradrenaline release, and this is prevented by b-receptor antagonists local generation of angiotensin II within vascular tissues is stimulated by b2-agonists.

cardio-selective: b1 blockers atenolol, metoprolol b1 blockers with ISA acebutol b1 + a1 blockers labetalol, carvedilol

cardio non-selective: b1 + b2 blockers metiprolol, propranolol,

nadolol b1 + b2 blockers with ISA pindolol, bopindolol

b-adrenoreceptor antagonists

Note: Partial agonist activity (intrinsic sympathomimetic activity – ISA) - may be an advantage in treating patients with asthma because these drugs will cause bronchodilation; they have moderate (lower) effect on lipid metabolism, cause lesser vasospasms and negative inotropic effect

Adverse effects

Cardiovascular adverse effects, which are extension of the betablockade, include:- bradycardia- antrioventricular blockade- congestive heart failure (unstable)- asthmatic attacks (in patients with airway disease)- premonitory symptoms of hypoglycemia from insulin overdosage

(eg, tachycardia, tremor and anxiety, may be marked)- CNS adverse effects - sedation, fatigue, and sleep alterations.

b-adrenoreceptor antagonists

Hypertension & regulation of blood pressure

Anatomic sites of blood pressure control

Baroreflexes (mediated by autonomic nerves)

Humoral mechanisms (include: RAAS system and local release of hormones from vascular endothelium, such as, NO, endothelin 1)

Hypertension & regulation of blood pressure

Sense the stretch of the vessel walls• from a reclining to an upright posture;• reduction of peripheral vacular resistance;• Reduction in intravascular volume;-

A. Postural baroreflex: responsible for rapid , moment to moment adjustments in blood pressure.

Hypertension & regulation of blood pressure

B. Renin-Angiotensin-Adolsteron (RAAS)

This is responsible for long-term blood pressure control.

Redistribution of renal blood flow

Angiotensin II

I. Basic pharmacology of antihypertension drugs

1. Diuretics: depleting the sodium and reducing blood volume and perhaps by other mechanisms.

2. Sympathoplegic agents: reducing peripheral vascular resistance, inhibiting cardic output, increasing venous pooling.

3. Direct vasodilators: relaxing vacular smooth muscle, dilaing resistance vessels and/or increasing capacitance.

4. Agents that block RAAS: reduce peripheral vacular resistance and blood volume.

I. Basic pharmacology of antihypertension agents

Sodium restriction is very preventive in the control of blood pressure. It is a nontoxic and therapeutic measure.

1) Pharmacological roles (1) Diurectic action: In the early stage: reducing blood volume and cardiac

output; In the late stage: reduce peripheral vascular resistance (by

reducing the Na+; reduce Na+-Ca2+ exchange in vascular smooth muscle cells (Ca2+i , peripheral resistance )

(2) Non diurectic action: direct vasodilating, e.g. Indapamide, a non-thiazide sullfonamide diuretic with both diuretic and vasodilator activity; Amiloride inhibits smooth muscle responses to contractile stimuli.

1. Diuretics

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Diuretics commonly used1-47

Diuretics Drugs causing net loss of Na+ and water in urine Mechanism of antihypertensive action:

Initially: diuresis – depletion of Na+ and body fluid volume – decrease in cardiac output

Subsequently after 4 - 6 weeks, Na+ balance and CO is regained by 95%, but BP remains low!

Q: Why? Answer: reduction in total peripheral resistance (TPR) due to deficit of little amount of Na+ and water (Na+ causes vascular stiffness)

Similar effect is seen with sodium restriction (low sodium diet)

Thiazide diuretics – adverse effects Adverse Effects:

Hypokalaemia – muscle pain and fatigue Hyperglycemia: Inhibition of insulin release due to K+ depletion (proinsulin

to insulin) – precipitation of diabetes Hyperlipidemia: rise in total LDL level – risk of stroke Hyperurecaemia: inhibition of urate excretion Sudden cardiac death – tosades de pointes (hypokalaemia) All the above metabolic side effects – higher doses (50 – 100 mg per day) But, its observed that these adverse effects are minimal with low doses

(12.5 to 25 mg) - Average fall in BP is 10 mm of Hg

Thiazide diuretics – current status Effects of low dose:

No significant hypokalaemia Low incidence of arrhythmia Lower incidence of hyperglycaemia, hyperlipidemia and hyperuricaemia Reduction in MI incidence Reduction in mortality and morbidity

JNC recommendation: JNC recommends low dose of thiazide therapy (12.5 – 25 mg per day) in essential

hypertension Preferably should be used with a potassium sparing diuretic as first choice in

elderly If therapy fails – another antihypertensive but do not increase the thiazide dose Loop diuretics are to be given when there is severe hypertension with retention of

body fluids

Diuretics K+ sparing diuretics:

Thiazide and K sparing diuretics are combined therapeutically – DITIDE (triamterene + benzthiazide) is popular one

Modified thiazide: indapamide Indole derivative and long duration of action (18 Hrs) – orally 2.5 mg dose It is a lipid neutral i.e. does not alter blood lipid concentration, but other

adverse effects may remain Loop diuretics:

Na+ deficient state is temporary, not maintained round –the-clock and t.p.r not reduced

Used only in complicated cases – CRF, CHF marked fluid retention cases

Selection of diuretcs

Nephron, a functional unit of kidney

Normally used in severe hypertension, in renal insufficiency and in cardiac failure or cirrhosis.

Normally used in mild or moderate hypertension with normal renal and cardiac function.

Useful to avoid excessive potassium depletion.

1. Diuretics

Be careful increase blood pressure

Dosing considerations (thiazide vs. Furosemide)

100 - 200 mg thiazide diuretics are more natriurectic but the same effect of anti-hypertension is the same as 25 – 50 mg thiazide diuretcs.

A threshold amount of body sodium depletion may be sufficient for anti-hypertensive efficacy.

The blood pressure response to loop diuretics continues to increase at doses many times greater than the usual therapeutic dose.

2) Clinical application: diuretics alone for mild or moderate essential hypertension. Combine with sympathoplegic and vasodilator drugs to control the tendency toward sodium retention caused by these agents.

1. Diuretics

Adverse effects of diuretcs

• Hypokalemia: K+ depletion (except for potassium – sparing diuretcs); hypokalemia may be hazardous in persons taking digitalis, who have chronic arrhythmias, acute myocardial infarction or left ventricular dysfunction.

Restriction of dietary Na+ intake will minimize K+ loss.• Mg2+ depletion;• Impair glucose tolerance, induce hyperglycemia;• Increase serum lipid concentrations, induce hyperlipidemia;• Hyperuricemia, precipitate gout;

1. Diuretics

2. Sympathoplegic agents

The antihypertensive effect of these agents used alone may be limited by retention of Na+ by the kidney and expansion of blood volume. So sympathoplegic antihypertensive drugs are most effective when used concomitantly with a diuretc.

Sedation, mental depression, sleep disturbance, dry mouth, analgesia

Inhibition of parasympathetic regulation, profound sympathetic blockade

Similar like surgical sympathectomy

More selective action

2. Sympathoplegic agents

1) Centrally acting sympathoplegic drugs

2) Ganglion blocking agents

3) Adrenergic neuron-blocking agents

4) Adrenoceptor antagonists

Adrenoceptor antagonists

b Receptor blockers: Propranolol(1) Mechanism & Sites of Action: nonselective –block in brain, kidney and heart etc.

Sympathoplegic agents

b Receptor blockers: Propranolol

(2) Clinical uses

A. Hypertension: all kinds of hypertension more effective in young patients than elderly useful in treating coexisting conditions such as

supraventricular tachycardia, previous myocardial infarction, angina pectoris, glaucoma and migraine headache

B. Other uses: angina pectoris; arrhythmias

Adrenooceptor antagonists

Sympathoplegic agents

b Receptor blockers: Propranolol(3) Side effectsA. Bradycardia or cardiac conduction disease (over inhibition);B. Asthma (Why);C. Peripheral vascular insufficiencyD. Diabetes

E. Withdrawal syndrome after prolonged regular use: nervousness, tachycardia, increased intensity of angina (even myocardial infarction), or increase of blood pressure;

Adrenooceptor antagonists

Sympathoplegic agents

b and a1 Receptor blockers

Labetalol 拉贝洛尔

Carvedilol 卡维地洛

Amosulalol 氨磺洛尔

Blocker effect:b>a1>>a2

Drugs that alter sympathetic nervous system function Adrenooceptor antagonists

Labetalol is formulated as a racemic mixture of four isomers

(S,S)- and (R,S)-isomers—are inactive

(S,R)- is a potent - a blocker (1)

(R,R)- is a potent - b blocker (3)

Blood pressure is lowered by reduction of systemic vascular resistance without significant alteration in heart rate or cardiac output.

Treating the hypertension of pheochromocytoma and hypertensive emergencies.

Adrenooceptor antagonists

Sympathoplegic agents

b and a1 Receptor blockers

Other b Receptor blockers:

Carvedilol S(–) isomer is a nonselective b-receptor blocker Both S(–) and R(+) isomers have approximately equal a-receptor blocking potency.

Adrenooceptor antagonists

Sympathoplegic agents

Nebivolol D –Nebivolol b1 blocker

L-Nevivolol causes vasoliating not mediated by a blocked.Has active metabolites

b and a1 Receptor blockers

Mild decrease of blood pressure Minimal changes in cardiac output and heart rate Used for all kinds of hypertension, including

hypertensive emergency Less adverse effects

Drugs that alter sympathetic nervous system function Adrenooceptor antagonists

Drugs that alter sympathetic nervous system function Adrenooceptor antagonists