Cardiovascular PharmacologyCardiovascular PharmacologyManagement of HypertensionManagement of Hypertension

Prof. Dr. Ahmed Abd El Salam Prof. Dr. Ahmed Abd El Salam

Cardiovascular PharmacologyCardiovascular PharmacologyManagement of hypertensionManagement of hypertension

Hypertension is a major health problem with Hypertension is a major health problem with prevalence rate of 25% among adults, prevalence rate of 25% among adults, increasing to 50% among those above 60 increasing to 50% among those above 60 years.years.Hypertension causes dangerous complications Hypertension causes dangerous complications (Target Organ Damage [TOD])(Target Organ Damage [TOD]) such as such as myocardial infarction, heart failure, aortic myocardial infarction, heart failure, aortic aneurysm, stroke and renal failure. These aneurysm, stroke and renal failure. These complications occur commonly in complications occur commonly in high risk high risk patientspatients as males, elderly, smokers, diabetics, as males, elderly, smokers, diabetics, and those with high cholesterol levels.and those with high cholesterol levels.

The cause of hypertension is unknown and only The cause of hypertension is unknown and only less than 5% of cases are secondary to renal less than 5% of cases are secondary to renal diseases, pheochromocytoma, diseases, pheochromocytoma, hyperaldosteronism, aortic coarctation, or hyperaldosteronism, aortic coarctation, or secondary to drugs secondary to drugs (drug-induced (drug-induced hypertension)hypertension) such as: such as:- Vasoconstrictors, e.g. phenylephrine or flu medicineVasoconstrictors, e.g. phenylephrine or flu medicine- Volume expanders, e.g. glucocorticoids, NSAIDs Volume expanders, e.g. glucocorticoids, NSAIDs

and oral contraceptives.and oral contraceptives.

Classification and Management Classification and Management of High Blood Pressureof High Blood Pressure

Blood Pressure Stage (Systolic/Diastolic)

No TODNo Risk Factors

TODOr > One Risk Factor

Or only DM

Prehypertension(130-140/85-90)

Lifestyle modification Drugs

Stage 1 Hypertension(140-160/90-100)

Lifestyle modification up to 12 months

Drugs

Stage 2 Hypertension(>160/>100)

Drugs Drugs

Isolated Systolic Hypertension(>160/<90)

Target Blood PressureTarget Blood Pressure

<140/90 in low-risk group<140/90 in low-risk group

<130/85 in high-risk group<130/85 in high-risk group

Lifestyle Modification Lifestyle Modification (Nonpharmacological Management of Hypertension)(Nonpharmacological Management of Hypertension)

Beneficial in reducing high blood pressure and Beneficial in reducing high blood pressure and its complications.its complications.

Reduces the dose requirement of Reduces the dose requirement of antihypertensive drugs.antihypertensive drugs.

Recommended in all hypertensives initially and Recommended in all hypertensives initially and with drug therapy.with drug therapy.

Lifestyle modification includes :-Lifestyle modification includes :-

(1)(1). Reduced dietary intake of Na+ and fat, . Reduced dietary intake of Na+ and fat, increased Ca2+ and K+ intake, together with increased Ca2+ and K+ intake, together with diet rich in fruits and vegetables and low-fat diet rich in fruits and vegetables and low-fat dairy products.dairy products.

(2)(2). Weight reduction for overweight patients.. Weight reduction for overweight patients.

(3)(3). Regular physical exercise.. Regular physical exercise.

(4)(4). Stopping smoking and reducing alcohol . Stopping smoking and reducing alcohol

intakeintake

Classification of Antihypertensive DrugsClassification of Antihypertensive Drugs

Angiotensin II

3. Sympatholytics

1. Diuretics

6. Calcium Channel Blockers 7. Direct Vasodilators

5. Angiotensin Receptor Blockers (ARBs)

4. Angiotensin Converting EnzymeInhibitors (ACEIs)

2. Blockers

Vasodilators

Vasospasm

NE early late

BP = COP

TPR×

Centrally-acting

1-blockers

NB:NB: Hypertensive patients can be classified into salt-Hypertensive patients can be classified into salt-

sensitive and salt-resistant patients.sensitive and salt-resistant patients.

Salt-sensitiveSalt-sensitive hypertension is more common in hypertension is more common in elderly, obese, black, and patients with renal elderly, obese, black, and patients with renal disease. These patients have impaired renal disease. These patients have impaired renal Na+ excretion leading to Na+ retention with Na+ excretion leading to Na+ retention with increased Na+-Ca2+ exchange and increased Na+-Ca2+ exchange and vasoconstriction and vasoconstriction and low renin statuslow renin status..

Hypertension in these patients gives better Hypertension in these patients gives better response to diuretics and calcium channel response to diuretics and calcium channel blockers with poor response to blockers with poor response to B-blockers and blockers and ACEIs which act mainly in high-renin status.ACEIs which act mainly in high-renin status.

I. DiureticsI. Diuretics

Mechanism of ActionMechanism of Action

InitiallyInitially, they act by reducing plasma volume , they act by reducing plasma volume and COP, and COP, followed byfollowed by vasodilation and vasodilation and reduction in peripheral vascular resistance.reduction in peripheral vascular resistance.

AdvantagesAdvantages

Reduce mortality, stroke and cardiovascular Reduce mortality, stroke and cardiovascular complications of hypertension.complications of hypertension.

The least expensive antihypertensives.The least expensive antihypertensives.

IndicationsIndications1st choice in uncomplicated hypertension.1st choice in uncomplicated hypertension.Specially indicated in:Specially indicated in:

1. Systolic hypertension.1. Systolic hypertension. 2. Hypertension in elderly, black and obese patients 2. Hypertension in elderly, black and obese patients

(salt-sensitive).(salt-sensitive). 3. Hypertension complicated with heart failure.3. Hypertension complicated with heart failure.

Combined with other antihypertensives to potentiate Combined with other antihypertensives to potentiate their effect:their effect:

1. Control edema of vasodilators.1. Control edema of vasodilators. 2. Reduce plasma volume → increase renin and 2. Reduce plasma volume → increase renin and

potentiate the hypotensive action of ACEIs and b potentiate the hypotensive action of ACEIs and b blockers, especially in black old patients.blockers, especially in black old patients.

– Thiazides are the preferred diuretics for hypertension because in single daily dose they cause persistent volume depletion which is required to lower BP; whereas once daily dose of frusemide is inadequate as it causes temporary Na+ loss.

– Thiazides tend to retain Ca2+ → ↓ risk of bone fracture in the elderly.

Preparations and DosagePreparations and Dosage

Hydrochlorothiazide:Hydrochlorothiazide: low (12.5 mg) or lower low (12.5 mg) or lower (6.25 mg) dose combined with an ACEI or a b (6.25 mg) dose combined with an ACEI or a b blocker has adequate antihypertensive effect blocker has adequate antihypertensive effect with fewer side effects.with fewer side effects.Indapamide:Indapamide: a thiazide-like agent with more a thiazide-like agent with more vasodilator effect and less side effects vasodilator effect and less side effects especially in low-dose (1.25 mg) slow-release especially in low-dose (1.25 mg) slow-release preparations. preparations. Frusemide:Frusemide: orally 2-3 times daily in orally 2-3 times daily in hypertension with renal impairment in which hypertension with renal impairment in which case thiazide diuretics are not effective due to case thiazide diuretics are not effective due to decreased GFR.decreased GFR.

Side EffectsSide Effects-:-:

1. Metabolic Side Effects1. Metabolic Side Effects

Hyperuricemia - hyperglycemia -hyperlipidemia.Hyperuricemia - hyperglycemia -hyperlipidemia.

2. Electrolyte Disturbances2. Electrolyte Disturbances

Hypokalemia - hyponatremia -hypomagnesemia.Hypokalemia - hyponatremia -hypomagnesemia.

These side effects can be minimized by:These side effects can be minimized by:--

a. Low-sodium and high-potassium diet.a. Low-sodium and high-potassium diet.

b. Using low dose of thiazide especially when b. Using low dose of thiazide especially when combined with b blockers to avoid unfavorable combined with b blockers to avoid unfavorable additive metabolic effects.additive metabolic effects.

c. Combination with spironolactone in cardiac c. Combination with spironolactone in cardiac patients to avoid the dangerous effects of patients to avoid the dangerous effects of hypokalemia and hypomagnesemia.hypokalemia and hypomagnesemia.

d. Combination with ACEIs which may neutralize d. Combination with ACEIs which may neutralize these effects.these effects.

3. Impotence (common).3. Impotence (common).

4. Sulfonamide hypersensitivity reactions (rare) 4. Sulfonamide hypersensitivity reactions (rare) as jaundice, pancreatitis and blood disorders.as jaundice, pancreatitis and blood disorders.

II. B-Adrenergic BlockersII. B-Adrenergic Blockers

Mechanism of ActionMechanism of Action-: -:

Initially, they decrease COP without effective Initially, they decrease COP without effective drop in BP due to reflex vasospasm with early drop in BP due to reflex vasospasm with early increase in TPR.increase in TPR.

Later, they decrease TPR and BP through:Later, they decrease TPR and BP through:

a. ↓ Renin release.a. ↓ Renin release.

b. ↓ NE release by central and peripheral effects.b. ↓ NE release by central and peripheral effects.

c. ↑ PG causing VD.c. ↑ PG causing VD.

AdvantagesAdvantages

Decrease cardiovascular mortality & morbidity Decrease cardiovascular mortality & morbidity and protect against coronary heart disease.and protect against coronary heart disease.

Relatively not expensive.Relatively not expensive.

IndicationsIndications

Alternative to diuretics as 1st line treatment of Alternative to diuretics as 1st line treatment of uncomplicated hypertension.uncomplicated hypertension.

Used in young hypertensives where COP is high.Used in young hypertensives where COP is high.

Hypertension associated with coronary heart Hypertension associated with coronary heart disease.disease.

Preparations and DosagePreparations and DosageThe ideal antihypertensive B-blocker would be The ideal antihypertensive B-blocker would be long-acting (once-daily) and b1-selective.long-acting (once-daily) and b1-selective.It is best to start with low dose to lessen the It is best to start with low dose to lessen the initial side effects as fatigue and bradycardia initial side effects as fatigue and bradycardia due to ↓ COP.due to ↓ COP.If the ordinary dose is inadequate, it is better to If the ordinary dose is inadequate, it is better to combine with another drug rather than to combine with another drug rather than to increase the dose.increase the dose.

Atenolol Atenolol 25-100 mg25-100 mgBisoprolol Bisoprolol 2.5-10 mg.2.5-10 mg.Metoprolol Metoprolol 50-200 mg.50-200 mg.

B-Blocker Combinations in HypertensionB-Blocker Combinations in Hypertension1. b Blockers plus Diuretics1. b Blockers plus Diuretics

Diuretics acting by Na+ loss increase renin secretion → Diuretics acting by Na+ loss increase renin secretion → VC by angiotensin II thus offsetting their hypotensive VC by angiotensin II thus offsetting their hypotensive effect. b Blockers inhibit renin release → potentiate the effect. b Blockers inhibit renin release → potentiate the hypotensive effect of diuretics. On the other hand, hypotensive effect of diuretics. On the other hand, diuretics, by increasing renin level, potentiate the diuretics, by increasing renin level, potentiate the hypotensive effect of b blockers in low-renin hypotensive effect of b blockers in low-renin hypertensives as black elderly patients.hypertensives as black elderly patients.

For initial therapy of hypertension, the lowest effective For initial therapy of hypertension, the lowest effective dose of both drugs [bisoprolol (2.5 mg) and dose of both drugs [bisoprolol (2.5 mg) and hydrochlorothiazide (6.25 mg)] is recommended to avoid hydrochlorothiazide (6.25 mg)] is recommended to avoid possible additive metabolic side effects such as possible additive metabolic side effects such as hyperglycemia and hyperlipidemia.hyperglycemia and hyperlipidemia.

2. B-Blockers plus Dihydropyridine (DHP) 2. B-Blockers plus Dihydropyridine (DHP) Ca2+ Channel BlockersCa2+ Channel Blockers

DHP Ca2+ channel blockers induce vasodilator DHP Ca2+ channel blockers induce vasodilator effect and reflex tachycardia, offsetting a effect and reflex tachycardia, offsetting a possible vasospasm and bradycardia induced possible vasospasm and bradycardia induced by b blockers.by b blockers.

Side Effects Side Effects (Less with B1-selective)(Less with B1-selective)::

1. Bronchospasm, cold extremities.1. Bronchospasm, cold extremities.

2. Metabolic: glucose intolerance, dyslipidemia.2. Metabolic: glucose intolerance, dyslipidemia.

3. Bradycardia, heart block.3. Bradycardia, heart block.

4. CNS depression, sense of fatigue.4. CNS depression, sense of fatigue.

5. Impotence.5. Impotence.

III. Calcium Channel BlockersIII. Calcium Channel Blockers

There are two main types of voltage-dependent There are two main types of voltage-dependent Ca2+ channels:Ca2+ channels:--

1. L-type (Long-lasting) with slow inactivation 1. L-type (Long-lasting) with slow inactivation and high conductivity.and high conductivity.

2. T-type (Transient) with fast inactivation 2. T-type (Transient) with fast inactivation and low conductivity.and low conductivity.

Ca2+ channel blockers act on α1 subunit of L-Ca2+ channel blockers act on α1 subunit of L-type channel that is located in conductive type channel that is located in conductive tissues (SAN & AVN) cardiac myocytes and tissues (SAN & AVN) cardiac myocytes and vascular smooth muscle including coronaries.vascular smooth muscle including coronaries.

Classification, Actions, Uses and Adverse Classification, Actions, Uses and Adverse Reactions of Calcium Channel BlockersReactions of Calcium Channel Blockers

ClassClass ActionsActions UsesUses Adverse ReactionsAdverse Reactions

I. Dihydropyridine I. Dihydropyridine (DHP)(DHP)

A. Short-actingA. Short-acting

NifedipineNifedipine

B. Long-actingB. Long-acting

AmlodipineAmlodipine

(5-10 mg once daily)(5-10 mg once daily)

Vessels > Myocardium > Vessels > Myocardium > SAN, AVNSAN, AVN

DHP induce strong DHP induce strong coronary & peripheral coronary & peripheral vasodilation with less vasodilation with less cardiac effect.cardiac effect.

Lower BP with reflex Lower BP with reflex sympathetic activation:sympathetic activation:

- Marked with nifedipine → - Marked with nifedipine → ↑↑ HR.↑↑ HR.

- Less with amlodipine → - Less with amlodipine → minimal HR changeminimal HR change

1. Hypertension.1. Hypertension.

2. Peripheral 2. Peripheral vascular disease vascular disease (e.g., Raynaud's (e.g., Raynaud's phenomenon).phenomenon).

1.1. Marked Marked tachycardia & tachycardia & acute acute myocardial myocardial ischemia in ischemia in coronary coronary disease disease (nifedipine).(nifedipine).

2. Hypotension.2. Hypotension.

3. Headache, flushing, 3. Headache, flushing, lower limb lower limb edema.edema.

II. Non-DHPII. Non-DHP

A. PhenylalkylaminesA. Phenylalkylamines

Verapamil Verapamil

(240 mg SR once daily)(240 mg SR once daily)

B. BenzothiazepinesB. Benzothiazepines

DiltiazemDiltiazem

(Heart-Rate Lowering)(Heart-Rate Lowering)

SAN, AVN > Myocardium = SAN, AVN > Myocardium = VesselsVessels

Inhibition of SAN & AVN → Inhibition of SAN & AVN → ↓ HR.↓ HR.

-ve inotropic effect.-ve inotropic effect.

Less VD effect → lower BP Less VD effect → lower BP with mild reflex with mild reflex sympathetic activation, sympathetic activation, partially offsetting the partially offsetting the direct cardiac effect direct cardiac effect

(especially verapamil).(especially verapamil).

1. SV arrhythmia:1. SV arrhythmia:

- Prophylaxis of PSVT - Prophylaxis of PSVT (( nodal reentry). nodal reentry).

- HR control in chronic - HR control in chronic AF.AF.

2. HOCM (↓ outflow 2. HOCM (↓ outflow obstruction).obstruction).

3. Angina pectoris 3. Angina pectoris (effort or vasospastic).(effort or vasospastic).

4. Hypertension.4. Hypertension.

1. Bradycardia & 1. Bradycardia & heart block.heart block.

2. HF (especially 2. HF (especially with diltiazem).with diltiazem).

3. Constipation 3. Constipation (only with (only with

verapamil).verapamil).

Calcium Channel Blockers for Calcium Channel Blockers for HypertensionHypertension

Mechanism of ActionMechanism of Action

Peripheral VD and ↓ TPR.Peripheral VD and ↓ TPR.

Diuretic action secondary to ↑ renal blood flow.Diuretic action secondary to ↑ renal blood flow.

↓ ↓ Aldosterone secretion.Aldosterone secretion.

AdvantagesAdvantages

No metabolic side effects (no changes in No metabolic side effects (no changes in glucose, lipid or uric acid levels).glucose, lipid or uric acid levels).

No affection of sexual activity.No affection of sexual activity.

May improve renal function.May improve renal function.

IndicationsIndications : : 2nd Choice after diuretics in elderly 2nd Choice after diuretics in elderly hypertensives or in isolated systolic hypertensives or in isolated systolic hypertension.hypertension.2nd Choice after 2nd Choice after b blockers in b blockers in hypertensives hypertensives with coronary heart disease.with coronary heart disease.Hypertension with peripheral vascular disease Hypertension with peripheral vascular disease (PVD).(PVD).Hypertension with renal impairment.Hypertension with renal impairment.

Preparations and DosagePreparations and Dosage: : Amlodipine Amlodipine 5 mg once daily.5 mg once daily.Verapamil Verapamil 240 mg SR once daily. 240 mg SR once daily.

IV. Angiotensin-Converting Enzyme (ACE) InhibitorsIV. Angiotensin-Converting Enzyme (ACE) Inhibitors

Angiotensin II

Bradykinin

Inactive peptide

ACE

Angiotensinogen

Renin

Angiotensin I

AT2 ReceptorsProtective VD.

Anti-proliferative.

AT4 Receptors?Prothrombotic:↑ Fibrinogen.↑ Plasminogen activator inhibitor I (PAI1)

AT1 ReceptorsDirect VC. Sympathetic (central + peripheral).↑ Aldosterone (Na+ retention).↑ ADH (water retention).

Proliferation of myocytes in heart and vessel wall.

Mechanism of Action of ACEIs: ACEIs have Mechanism of Action of ACEIs: ACEIs have dual vasodilator action by:dual vasodilator action by:

1. ↓ Angiotensin II formation which mediates most of its 1. ↓ Angiotensin II formation which mediates most of its effects through activation of AT1 receptors (inhibits effects through activation of AT1 receptors (inhibits vasospasm, salt & water retention & cardiac & vascular vasospasm, salt & water retention & cardiac & vascular remodeling induced by angiotensin II).remodeling induced by angiotensin II).↓ ↓ Activity of angiotensin II at AT2 receptors → Activity of angiotensin II at AT2 receptors → minimizes vasodilator effect of ACEIs (a disadvantage minimizes vasodilator effect of ACEIs (a disadvantage compared to ARBs). compared to ARBs). ↓ ↓ Activity of angiotensin II at AT4 receptors → ↓its Activity of angiotensin II at AT4 receptors → ↓its prothrombotic effect mediated by ↑ fibrinogen & PAI1 prothrombotic effect mediated by ↑ fibrinogen & PAI1 (an advantage over ARBs).(an advantage over ARBs).

2. ↑ Bradykinin through inhibition of its deactivation → 2. ↑ Bradykinin through inhibition of its deactivation → direct VD & release of potent vasodilator PGs and NO direct VD & release of potent vasodilator PGs and NO from vascular endothelium.from vascular endothelium.

Therapeutic Uses of ACEIsTherapeutic Uses of ACEIs

I. Cardiovascular UsesI. Cardiovascular Uses

ACE inhibitors have unique effects in ACE inhibitors have unique effects in preventing and treating preventing and treating cardiovascular cardiovascular diseasesdiseases. They act on sequential events . They act on sequential events from risk factors to left ventricular failure.from risk factors to left ventricular failure.

The main cardiovascular indications of ACEIs are:The main cardiovascular indications of ACEIs are:

Major risk factorsMajor risk factors

1. Hypertension: ↓ BP, 1. Hypertension: ↓ BP, } } Major risk factors

↓ ↓ LV hypertrophyLV hypertrophy

2. Ischemic heart disease: inhibits atherogenesis and 2. Ischemic heart disease: inhibits atherogenesis and thrombogenesis.thrombogenesis.

3. Myocardial infarction:3. Myocardial infarction:

Early administration during acute attacks prevents Early administration during acute attacks prevents sudden death by preventing arrhythmia induced by sudden death by preventing arrhythmia induced by hypokalemia and sympathetic overactivity.hypokalemia and sympathetic overactivity.

Decrease postinfarction remodeling caused by Decrease postinfarction remodeling caused by aldosterone and prevent heart failure.aldosterone and prevent heart failure.

4. Heart failure: used in all stages of heart failure.4. Heart failure: used in all stages of heart failure.

Major risk factors

II. Nephropathy (diabetic or nondiabetic)II. Nephropathy (diabetic or nondiabetic)

ACEIs decrease intraglomerular pressure, ACEIs decrease intraglomerular pressure, progressive glomerulosclerosis, and progressive glomerulosclerosis, and proteinuria and delay the onset of renal proteinuria and delay the onset of renal failure.failure.

ADVERSE REACTIONSADVERSE REACTIONS

Related to↑ Bradykinin

Related to ↓ Angiotensin II

Related to High Dose Captopril

(immune-base)

HypotensionRenal impairmentHyperkalemia (↓ aldosterone)

Skin allergyNeutropeniaProteinuriaLoss of taste.

Acute angioedema (early)Chronic dry cough (late).

1. Cough 1. Cough Common side effect which may disappear after 4 Common side effect which may disappear after 4

months. Addition of low dose of nifedipine may months. Addition of low dose of nifedipine may decrease cough. If not, shift to angiotensin receptor decrease cough. If not, shift to angiotensin receptor blockers (ARBs).blockers (ARBs).

2. Angioedema2. Angioedema Rare but may be fatal. Epinephrine and intubation Rare but may be fatal. Epinephrine and intubation

may be needed.may be needed.3. Hypotension and reversible renal failure3. Hypotension and reversible renal failure More common in high renin states such as in More common in high renin states such as in

patients on diuretics, or those with heart failure or patients on diuretics, or those with heart failure or renal artery stenosis.renal artery stenosis.

4. Hyperkalemia4. Hyperkalemia Occurs with co-administration of b blockers, Occurs with co-administration of b blockers,

aldosterone antagonist or renal impairment.aldosterone antagonist or renal impairment.

Classification of ACEIsClassification of ACEIs

Class ICaptopril (SH)

Class IIEnalapril - PerindoprilRamipril - Fosinopril

Class IIILisinopril

Class I (Captopril) :Class I (Captopril) :Not a prodrug.Not a prodrug. Rapid onset & short duration (t½ 4-6 h), can be given Rapid onset & short duration (t½ 4-6 h), can be given sublingually in severe hypertensionsublingually in severe hypertension↓ ↓ Nitrate tolerance (due to its SH group).Nitrate tolerance (due to its SH group).

Class II (Enalapril - Perindopril - Ramipril - Fosinopril):Class II (Enalapril - Perindopril - Ramipril - Fosinopril):Prodrugs (activated first in liver).Prodrugs (activated first in liver). Slow onset & long duration (given once/day).Slow onset & long duration (given once/day).Have carboxyl group not SH group with absence of Have carboxyl group not SH group with absence of immune base side effects of captopril.immune base side effects of captopril.Fosinopril has phosphoryl group instead of carboxyl Fosinopril has phosphoryl group instead of carboxyl group with dual route of excretion (hepatic & renal) → group with dual route of excretion (hepatic & renal) → no dose adjustment in renal failure.no dose adjustment in renal failure.

Classification (contin)Classification (contin)

Class III (lisinopril) :Class III (lisinopril) :– Not a prodrug.Not a prodrug.– Long duration.Long duration.– Water soluble, not metabolized in liver and Water soluble, not metabolized in liver and

excreted unchanged by the kidney → given in excreted unchanged by the kidney → given in liver disease.liver disease.

ACE Inhibitors in HypertensionACE Inhibitors in Hypertension

Mechanism of ActionMechanism of Action

1. Vasodilation due to ↓ angiotensin II & ↑ 1. Vasodilation due to ↓ angiotensin II & ↑ vasodilator BK, PGs & NO.vasodilator BK, PGs & NO.

2. Anti-adrenergic effect by blocking central & 2. Anti-adrenergic effect by blocking central & peripheral adrenergic activity of angiotensin peripheral adrenergic activity of angiotensin II (thus ACEIs decrease BP without reflex II (thus ACEIs decrease BP without reflex tachycardia).tachycardia).

3. Inhibition of aldosterone → Na+ loss.3. Inhibition of aldosterone → Na+ loss.

AdvantagesAdvantages1.1. ↓ Cardiovascular mortality and morbidity. ↓ Cardiovascular mortality and morbidity.

2.2. Protect renal function especially in diabetics. Protect renal function especially in diabetics.

3.3. No metabolic side effects (no effect on glucose, lipid No metabolic side effects (no effect on glucose, lipid or uric acid).or uric acid).

4.4. May improve glucose intolerance in insulin resistance. May improve glucose intolerance in insulin resistance.

5.5. No changes in heart rate. No changes in heart rate.

IndicationsIndications1.1. Diabetic hypertensives. Diabetic hypertensives.

2.2. Hypertension with nephropathy in diabetics or Hypertension with nephropathy in diabetics or nondiabetics.nondiabetics.

3.3. Hypertension in HF or after myocardial infarction. Hypertension in HF or after myocardial infarction.

V. Angiotensin II Receptor Blockers (ARBs)V. Angiotensin II Receptor Blockers (ARBs)(Losartan - Valsartan - Telmisartan)(Losartan - Valsartan - Telmisartan)

They block angiotensin II receptor type I (AT1) responsible for They block angiotensin II receptor type I (AT1) responsible for most of the damaging effects of angiotensin II (see figure p. most of the damaging effects of angiotensin II (see figure p. 179).179).

Advantages of ARBs over ACEIsAdvantages of ARBs over ACEIs1.1. Antagonize AG II formed by both ACE & non-ACE pathway Antagonize AG II formed by both ACE & non-ACE pathway

(e.g. chymase).(e.g. chymase).2.2. They are able to avoid hormonal "escape" (↑ renin & They are able to avoid hormonal "escape" (↑ renin &

angiotensin II) which may occur during prolonged angiotensin II) which may occur during prolonged administration of ACEIs.administration of ACEIs.

3.3. They block the hypersensitivity of AT1 receptor caused by They block the hypersensitivity of AT1 receptor caused by insulin or LDL.insulin or LDL.

4.4. Blocking AT1 receptor directs angiotensin II to AT2 receptor Blocking AT1 receptor directs angiotensin II to AT2 receptor which has vasodilator action and antiproliferative effect.which has vasodilator action and antiproliferative effect.

5.5. No production of bradykinin which may be responsible for No production of bradykinin which may be responsible for angioedema and cough seen with ACEIs.angioedema and cough seen with ACEIs.

Disadvantages of ARBsDisadvantages of ARBs1.1. Lack of protective effect of bradykinin due to Lack of protective effect of bradykinin due to

NO & PGs formation.NO & PGs formation.

2.2. Activation of AT4 receptor responsible for Activation of AT4 receptor responsible for prothrombotic effect with increased fibrinogen, prothrombotic effect with increased fibrinogen, plasminogen activator inhibitor I.plasminogen activator inhibitor I.

VI. Direct VasodilatorsVI. Direct VasodilatorsHydralazineHydralazine

Mechanism of ActionMechanism of ActionIt is an arteriolar vasodilator that may act as a K+ It is an arteriolar vasodilator that may act as a K+ channel opener with hyperpolarization of vascular channel opener with hyperpolarization of vascular membrane which prevents Ca2+ influx into the wall membrane which prevents Ca2+ influx into the wall of blood vessels.of blood vessels.

PharmacokineticsPharmacokineticsIt is rapidly absorbed from the gut.It is rapidly absorbed from the gut.It is metabolized in the liver by acetylation. Fast It is metabolized in the liver by acetylation. Fast acetylators need large dose, while slow acetylators acetylators need large dose, while slow acetylators may develop lupus syndrome.may develop lupus syndrome.It is excreted by the kidney and the dose should be It is excreted by the kidney and the dose should be reduced in renal disease.reduced in renal disease.

Indications :-Indications :-1. Hypertension1. Hypertensiona. IV hydralazine is the drug of choice in severe a. IV hydralazine is the drug of choice in severe

hypertension with pregnancy.hypertension with pregnancy.b. The chronic use of hydralazine in hypertension is b. The chronic use of hydralazine in hypertension is

associated with rapid tolerance due to reflex associated with rapid tolerance due to reflex activation of the sympathetic and renin-angiotensin activation of the sympathetic and renin-angiotensin systems resulting in salt retention and reflex systems resulting in salt retention and reflex tachycardia. So it is often used with diuretics and b tachycardia. So it is often used with diuretics and b blockers.blockers.

2. Congestive Heart Failure2. Congestive Heart FailureIt is not used alone but usually combined with It is not used alone but usually combined with nitrates.nitrates.It potentiates the effect of nitrates by reducing It potentiates the effect of nitrates by reducing afterload and by reducing nitrate tolerance by afterload and by reducing nitrate tolerance by decreasing free radical formation.decreasing free radical formation.

3. Mitral Regurge3. Mitral Regurge

Hydralazine, by decreasing peripheral Hydralazine, by decreasing peripheral resistance, increases forward stroke volume resistance, increases forward stroke volume and decreases regurgitant volume.and decreases regurgitant volume.

Adverse EffectsAdverse Effects

Salt retention and edema.Salt retention and edema.

Reflex tachycardia.Reflex tachycardia.

Lupus syndrome.Lupus syndrome.

Sodium NitroprussideSodium NitroprussideMechanism of ActionMechanism of Action

It is a donor of nitric oxide (NO) that increases the level It is a donor of nitric oxide (NO) that increases the level of cGMP which induces vasodilation by inhibiting Ca2+ of cGMP which induces vasodilation by inhibiting Ca2+ influx into the wall of blood vessels.influx into the wall of blood vessels.

Pharmacological PropertiesPharmacological PropertiesIt has a potent direct vasodilator (arteriolar and It has a potent direct vasodilator (arteriolar and venular) effect decreasing both preload and afterload.venular) effect decreasing both preload and afterload.It has an immediate effect and very short duration of It has an immediate effect and very short duration of action (2 minutes).action (2 minutes).It is converted in the body into cyanomethemoglobin It is converted in the body into cyanomethemoglobin and free cyanide which is metabolized into thiocyanate and free cyanide which is metabolized into thiocyanate in liver and excreted by the kidney.in liver and excreted by the kidney.

Indications :-Indications :-1. Hypertensive Emergencies1. Hypertensive Emergencies

It is useful in most hypertensive emergencies as It is useful in most hypertensive emergencies as hypertensive encephalopathy, severe hypertension hypertensive encephalopathy, severe hypertension with acute HF and dissecting aortic aneurysm.with acute HF and dissecting aortic aneurysm.

2. Severe Acute Heart Failure2. Severe Acute Heart FailureIt is useful in severe acute HF especially with mitral It is useful in severe acute HF especially with mitral and aortic regurgitation provided the arterial and aortic regurgitation provided the arterial pressure is reasonable.pressure is reasonable.It may be used in acute HF complicating myocardial It may be used in acute HF complicating myocardial infarction, cardiac surgery or acute exacerbation of infarction, cardiac surgery or acute exacerbation of chronic HF.chronic HF.Nitroprusside is now replaced by safer drugs as Nitroprusside is now replaced by safer drugs as nitroglycerin or milrinone (an inotropodilator).nitroglycerin or milrinone (an inotropodilator).

ToxicityToxicity1. Cyanide Toxicity1. Cyanide ToxicityOccurs especially when it is given at high doses for Occurs especially when it is given at high doses for long periods, particularly in liver and renal diseases long periods, particularly in liver and renal diseases which limit cyanide clearance.which limit cyanide clearance.It varies from mild abdominal pain & vomiting to It varies from mild abdominal pain & vomiting to neurological symptoms as headache, confusion neurological symptoms as headache, confusion and convulsions up to unexplained death.and convulsions up to unexplained death.

TreatmentTreatmentSodium nitrate 3% solution 2.5 ml/min for 5 min, Sodium nitrate 3% solution 2.5 ml/min for 5 min, followed by sodium thiosulfate 12.5 g in solution of followed by sodium thiosulfate 12.5 g in solution of 5% D/W over 10 minutes.5% D/W over 10 minutes.Overdose may cause severe hypotension and Overdose may cause severe hypotension and myocardial ischemia.myocardial ischemia.

Dosage:Dosage: 0.5-10 mg/kg/min IV infusion. 0.5-10 mg/kg/min IV infusion.

Precautions :-Precautions :-

a.a. Infusion rate needs careful titration against Infusion rate needs careful titration against BP, which must be continuously monitored to BP, which must be continuously monitored to avoid excessive hypotension (potentially avoid excessive hypotension (potentially fatal).fatal).

b.b. Avoid extravasation. Avoid extravasation.

c.c. Solution in normal saline should be freshly Solution in normal saline should be freshly prepared and then protected from light during prepared and then protected from light during infusion.infusion.

dd. Solution should be discarded when it is 4 . Solution should be discarded when it is 4 hours old or if it is discolored.hours old or if it is discolored.

VII. SympatholyticsVII. SympatholyticsThey include centrally-acting drugs and a1-They include centrally-acting drugs and a1-adrenoceptor blockers.adrenoceptor blockers.

Mechanism of Action of Centrally-Acting DrugsMechanism of Action of Centrally-Acting Drugs

ClonidineMethyldopa

RelmenidineMoxonidine

Central Sympathetic Discharge

Imidazoline Receptor

Rostral ventrolateral medulla (RVLM)

α2 Receptor

Nucleus tractus solitarius (NTS)

Salivary gland(Dryness)

Locus ceruleus(Sedation)

Sympatholytics used in HypertensionSympatholytics used in Hypertension

Centrally-Acting Drugs1-

Adrenoceptor Blockers

Imidazoline Receptor Agonists

●Relmenidine●Moxonidine

2-Receptor

Agonists●Methyldopa

Both Imidazoline& 2-Agonists

●Clonidine ●Prazosin●Doxazosin

Indications●Hypertension with

diabetes and/or dyslipidemia:

- Improve insulin sensitivity & lipid profile.

●Hypertension with pregnancy (1st-choice due to large established safety to fetus).

●Severe hypertension (induces rapid reduction of BP).

●Hypertension in patients with prostate hypertrophy.

Adverse Effects●Minimal (no

sedation or dryness are seen).

●Sedation●Dryness●Hepatotoxicity●Hemolytic anemia

●Sedation●Dryness●Bradycardia●Rebound ↑ BP on

sudden withdrawal.

●Postural hypotension & reflex tachycardia.

Hypertension in the elderlyHypertension in the elderly

Benefit from antihypetensive therapy is Benefit from antihypetensive therapy is evident up to at least 80 years of age.evident up to at least 80 years of age.

The thresholds for treatment are diastolic The thresholds for treatment are diastolic pressure averaging 90 mmHg and systolic pressure averaging 90 mmHg and systolic pressure averaging 160 mmHg.pressure averaging 160 mmHg.

A low dose of a thiazide is the drug of first A low dose of a thiazide is the drug of first choice, with addition of another choice, with addition of another antihypertensive when necessary.antihypertensive when necessary.

Isolated Systolic HypertensionIsolated Systolic Hypertension

ISH (systolic > or = 160, diastolic <90mmHg, ISH (systolic > or = 160, diastolic <90mmHg, should be lowered, even if diastolic hypertension should be lowered, even if diastolic hypertension is absent.is absent.Treatment with a low dose of a thiazide, with Treatment with a low dose of a thiazide, with addition of a B-blocker when necessary is addition of a B-blocker when necessary is effective.effective.A long-acting dihydropyridine CCB is given when A long-acting dihydropyridine CCB is given when a thiazide is contraindicated or not tolerated.a thiazide is contraindicated or not tolerated.Patients with severe postural Hypotension Patients with severe postural Hypotension should not receive BP lowering drugs.should not receive BP lowering drugs.

Hypertension in DiabetesHypertension in Diabetes

The aim should be to maintain SBP<130 and The aim should be to maintain SBP<130 and DBP<80 mmHg.DBP<80 mmHg.HTN is common in type 2 DM and treatment of HTN is common in type 2 DM and treatment of HTN prevents macrovascular and microvascular HTN prevents macrovascular and microvascular complications.complications.In type I DM, HTN usually indicates diabetic In type I DM, HTN usually indicates diabetic nephropathy.nephropathy.An ACEI or ARB may have a specific role in the An ACEI or ARB may have a specific role in the management of diabetic nephropathy.management of diabetic nephropathy.In type 2, an ACEI or ARB can delay In type 2, an ACEI or ARB can delay progression of microalbuminuria to nephropathy.progression of microalbuminuria to nephropathy.

Hypertension in renal diseaseHypertension in renal disease

The thresholds for treatment in are diastolic The thresholds for treatment in are diastolic pressure averaging 90 mmHg and systolic pressure averaging 90 mmHg and systolic pressure averaging 140 mmHg.pressure averaging 140 mmHg.Optimal BP is a SBP <130 and a DBP<80 Optimal BP is a SBP <130 and a DBP<80 mmHg if proteinuria exeeds 1 g in 24 h.mmHg if proteinuria exeeds 1 g in 24 h.Thiazides may be Thiazides may be ineffective ineffective and high doses of and high doses of loop diuretics may be required.loop diuretics may be required.Specific cautions apply to the use of ACEI in Specific cautions apply to the use of ACEI in renal impairment, but ACEIs may be effective.renal impairment, but ACEIs may be effective.DHP CCBs may be added.DHP CCBs may be added.

Hypertension in PregnancyHypertension in Pregnancy

High BP in pregnancy may usually be due to pre-existing High BP in pregnancy may usually be due to pre-existing essential HTN or to pre-eclampsia.essential HTN or to pre-eclampsia.Methyldopa is safe in pregnancy.Methyldopa is safe in pregnancy.B-blockers are effective and safe in the third trimester.B-blockers are effective and safe in the third trimester.Modified release preparations of nifedipine are also used Modified release preparations of nifedipine are also used in HTN in pregnancy.in HTN in pregnancy.IV labetalol or hydralazine can be used to control IV labetalol or hydralazine can be used to control hypertensive crisis.hypertensive crisis.Magnesium sulphate is the drug of choice to prevent Magnesium sulphate is the drug of choice to prevent seizures in pre-eclampsia and eclampsiaseizures in pre-eclampsia and eclampsia

Hypertensive CrisisHypertensive CrisisHypertensive crisis is defined as severe elevation in BP Hypertensive crisis is defined as severe elevation in BP usually a systolic BP exceeding 220 mmHg and/or a diastolic usually a systolic BP exceeding 220 mmHg and/or a diastolic BP greater than 120 mmHg.BP greater than 120 mmHg.It includes hypertensive emergencies and hypertensive It includes hypertensive emergencies and hypertensive urgencies.urgencies.

Hypertensive UrgenciesHypertensive UrgenciesIt is severe elevation of BP in absence of progressive target-It is severe elevation of BP in absence of progressive target-organ damage.organ damage.Immediate reduction in BP is not indicated and can be Immediate reduction in BP is not indicated and can be managed as outpatient case using combination of oral managed as outpatient case using combination of oral antihypertensives.antihypertensives.

Hypertensive EmergenciesHypertensive EmergenciesIt is severe elevation in BP with acute progressive target-It is severe elevation in BP with acute progressive target-organ damage.organ damage.It represents an acute life-threatening situation which requires It represents an acute life-threatening situation which requires ICU admission for immediate controlled reduction in BP using ICU admission for immediate controlled reduction in BP using IV drug therapy to avoid death or irreversible organ damage.IV drug therapy to avoid death or irreversible organ damage.

Clinical Conditions Associated with HypertensiveClinical Conditions Associated with Hypertensive Emergencies & their Drug Therapy :-Emergencies & their Drug Therapy :-

1. Malignant Hypertension1. Malignant HypertensionIt is associated with bilateral retinal hemorrhage and/or exudates It is associated with bilateral retinal hemorrhage and/or exudates with or without papilledema.with or without papilledema.Fenoldopam D1 agonist is the preferred drug, as it ↑ renal blood Fenoldopam D1 agonist is the preferred drug, as it ↑ renal blood flow.flow.Other drugs: labetalol, enalaprilat.Other drugs: labetalol, enalaprilat.

2. Hypertensive Encephalopathy2. Hypertensive Encephalopathy It is associated with neurological manifestations as headache, It is associated with neurological manifestations as headache, vomiting, visual disturbance, confusion or convulsions.vomiting, visual disturbance, confusion or convulsions.BP should be reduced gradually not to normal level to avoid BP should be reduced gradually not to normal level to avoid brain ischemia.brain ischemia.Preferred drugs: labetalol, nitroprusside.Preferred drugs: labetalol, nitroprusside.Nimodipine is used in subarachnoid hemorrhage → ↓ cerebral Nimodipine is used in subarachnoid hemorrhage → ↓ cerebral vasospasm.vasospasm.

3. Acute Coronary Syndrome (unstable 3. Acute Coronary Syndrome (unstable angina & myocardial infarction)angina & myocardial infarction)Nitroglycerin, esmolol are preferred drugs.Nitroglycerin, esmolol are preferred drugs.Nitroprusside is preserved for resistant cases Nitroprusside is preserved for resistant cases as it may ↓ coronary BF.as it may ↓ coronary BF.

4. Acute Left Ventricular Failure4. Acute Left Ventricular FailureEnalaprilat, nitroglycerin and nitroprusside are Enalaprilat, nitroglycerin and nitroprusside are preferred. preferred. b Blockers are avoided.b Blockers are avoided.

5. Dissecting Aortic Aneurysm5. Dissecting Aortic AneurysmDrugs used: esmolol and nitroprusside.Drugs used: esmolol and nitroprusside.

6. Excessive Circulating Catecholamines6. Excessive Circulating CatecholaminesOccurs in pheochromocytoma, clonidine withdrawal Occurs in pheochromocytoma, clonidine withdrawal and food interaction with MAO inhibitors.and food interaction with MAO inhibitors.Drugs used: phentolamine (plus b blockers) or Drugs used: phentolamine (plus b blockers) or labetalol (without b Bs)labetalol (without b Bs)

7. Eclampsia 7. Eclampsia Hydralazine, nitroglycerin, labetalol may be used.Hydralazine, nitroglycerin, labetalol may be used.

8. Perioperative 8. Perioperative Includes severe hypertension in patient requiring Includes severe hypertension in patient requiring immediate surgery or postoperative hypertension immediate surgery or postoperative hypertension (↑ risk of myocardial infarction). (↑ risk of myocardial infarction). Drugs used: nitroglycerin, esmolol, labetalol, Drugs used: nitroglycerin, esmolol, labetalol, nitroprusside.nitroprusside.

Parenteral Agents for Hypertensive EmergenciesParenteral Agents for Hypertensive EmergenciesAgent & Dose Indications

1. Nitroprusside 0.5-10 g/kg/min.

Most hypertensive emergencies 2ry to 1st-choice agents.

2. Nitroglycerin 0.5-20 g/kg/min.

Acute coronary syndrome. Acute left ventricular failure.

3. Labetalol 20 mg test dose. 40-80 mg bolus /15 min. 5-25 g/kg/min infusion.

Most hypertensive emergencies except acute HF (induces a small dose-related fall in BP).

4. Esmolol 50-250 g/kg/min.

Acute coronary syndrome, dissecting aortic aneurysm, perioperative hypertension (rapid & short-acting effect).

5. Hydralazine 5-10 mg (0.1-0.2 mg/kg) bolus/20 min.

Eclampsia.

6. Fenoldopam (D1 agonist)

0.2-0.5 g/kg/min

Malignant hypertension (↑ renal blood flow, but may cause reflex tachycardia)

7. Enalaprilat 0.65 mg test dose 1.25 mg/6h

Acute left ventricular failure.

8. Phentolamine 5-10 mg bolus/15 min.

Catecholamine excess.