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    Cardiovascular+pharmacology+drug+therapy+of+hypertension Cardiovascular+pharmacology+drug+therapy+of+hypertension Presentation Transcript

    • بسم الله الرحمن الرحيم
    • Cardiovascular PharmacologyManagement of Hypertension Dr. Mohamed saad
    • Cardiovascular PharmacologyManagement of hypertension
      Hypertension is a major health problem with
      prevalence rate of 25% among adults,
      increasing to 50% among those above 60
      years.
      Hypertension causes dangerous complications
      (Target Organ Damage [TOD]) such as
      myocardial infarction, heart failure, aortic
      aneurysm, stroke and renal failure. These
      complications occur commonly in high risk
      patients as males, elderly, smokers, diabetics,
      and those with high cholesterol levels.
    • The cause of hypertension is unknown and only less than 5% of cases are secondary to renal diseases, pheochromocytoma, hyperaldosteronism, aortic coarctation, or secondary to drugs (drug-induced hypertension) such as:
      • Vasoconstrictors, e.g. phenylephrine or flu medicine
      • Volume expanders, e.g. glucocorticoids, NSAIDs and oral contraceptives.
    • Classification and Management of High Blood Pressure
    • Target Blood Pressure
      <140/90 in low-risk group
      <130/85 in high-risk group
    • Lifestyle Modification (Nonpharmacological Management of Hypertension)
      Beneficial in reducing high blood pressure and its complications.
      Reduces the dose requirement of antihypertensive drugs.
      Recommended in all hypertensives initially and with drug therapy.
    • Lifestyle modification includes :-
      (1). Reduced dietary intake of Na+ and fat, increased Ca2+ and K+ intake, together with diet rich in fruits and vegetables and low-fat dairy products.
      (2). Weight reduction for overweight patients.
      (3). Regular physical exercise.
      (4). Stopping smoking and reducing alcohol
      intake
    • 3. Sympatholytics
      2. b Blockers
      NE
      early
      late
      Vasospasm
      Angiotensin II
      Vasodilators
      4. Angiotensin Converting Enzyme
      Inhibitors (ACEIs)
      1. Diuretics
      5. Angiotensin Receptor Blockers (ARBs)
      6. Calcium Channel Blockers
      7. Direct Vasodilators
      Classification of Antihypertensive Drugs
      Centrally-acting

      a1-blockers



      BP
      COP
      TPR
      =
      ×


    • NB:
      Hypertensive patients can be classified into salt-sensitive and salt-resistant patients.
      Salt-sensitive hypertension is more common in elderly, obese, black, and patients with renal disease. These patients have impaired renal Na+ excretion leading to Na+ retention with increased Na+-Ca2+ exchange and vasoconstriction and low renin status.
      Hypertension in these patients gives better response to diuretics and calcium channel blockers with poor response to B-blockers and ACEIs which act mainly in high-renin status.
    • I. Diuretics
      Mechanism of Action
      Initially, they act by reducing plasma volume and COP, followed by vasodilation and reduction in peripheral vascular resistance.
      Advantages
      Reduce mortality, stroke and cardiovascular complications of hypertension.
      The least expensive antihypertensives.
    • Indications
      1st choice in uncomplicated hypertension.
      Specially indicated in:
      1. Systolic hypertension.
      2. Hypertension in elderly, black and obese patients (salt-sensitive).
      3. Hypertension complicated with heart failure.
      Combined with other antihypertensives to potentiate their effect:
      1. Control edema of vasodilators.
      2. Reduce plasma volume -> increase renin and potentiate the hypotensive action of ACEIs and b 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 Dosage
      Hydrochlorothiazide: low (12.5 mg) or lower (6.25 mg) dose combined with an ACEI or a b blocker has adequate antihypertensive effect with fewer side effects.
      Indapamide: a thiazide-like agent with more vasodilator effect and less side effects especially in low-dose (1.25 mg) slow-release preparations.
      Frusemide: orally 2-3 times daily in hypertension with renal impairment in which case thiazide diuretics are not effective due to decreased GFR.
    • Side Effects-:
      1. Metabolic Side Effects
      Hyperuricemia - hyperglycemia -hyperlipidemia.
      2. Electrolyte Disturbances
      Hypokalemia - hyponatremia -hypomagnesemia.
    • These side effects can be minimized by:-
      a. Low-sodium and high-potassium diet.
      b. Using low dose of thiazide especially when combined with b blockers to avoid unfavorable additive metabolic effects.
      c. Combination with spironolactone in cardiac patients to avoid the dangerous effects of hypokalemia and hypomagnesemia.
      d. Combination with ACEIs which may neutralize these effects.
    • 3. Impotence (common).
      4. Sulfonamide hypersensitivity reactions (rare) as jaundice, pancreatitis and blood disorders.
    • II. B-Adrenergic Blockers
      Mechanism of Action-:
      Initially, they decrease COP without effective drop in BP due to reflex vasospasm with early increase in TPR.
      Later, they decrease TPR and BP through:
      a. ↓ Renin release.
      b. ↓ NE release by central and peripheral effects.
      c. ↑ PG causing VD.
    • Advantages
      Decrease cardiovascular mortality & morbidity and protect against coronary heart disease.
      Relatively not expensive.
      Indications
      Alternative to diuretics as 1st line treatment of uncomplicated hypertension.
      Used in young hypertensives where COP is high.
      Hypertension associated with coronary heart disease.
    • Preparations and Dosage
      The ideal antihypertensive B-blocker would be long-acting (once-daily) and b1-selective.
      It is best to start with low dose to lessen the initial side effects as fatigue and bradycardia due to ↓ COP.
      If the ordinary dose is inadequate, it is better to combine with another drug rather than to increase the dose.
      Atenolol 25-100 mg
      Bisoprolol 2.5-10 mg.
      Metoprolol 50-200 mg.
    • B-Blocker Combinations in Hypertension
      1. b Blockers plus Diuretics
      Diuretics acting by Na+ loss increase renin secretion -> VC by angiotensin II thus offsetting their hypotensive effect. b Blockers inhibit renin release -> potentiate the hypotensive effect of diuretics. On the other hand, diuretics, by increasing renin level, potentiate the hypotensive effect of b blockers in low-renin hypertensives as black elderly patients.
      For initial therapy of hypertension, the lowest effective dose of both drugs [bisoprolol (2.5 mg) and hydrochlorothiazide (6.25 mg)] is recommended to avoid possible additive metabolic side effects such as hyperglycemia and hyperlipidemia.
    • 2. B-Blockers plus Dihydropyridine (DHP) Ca2+ Channel Blockers
      DHP Ca2+ channel blockers induce vasodilator effect and reflex tachycardia, offsetting a possible vasospasm and bradycardia induced by b blockers.
    • Side Effects (Less with B1-selective):
      1. Bronchospasm, cold extremities.
      2. Metabolic: glucose intolerance, dyslipidemia.
      3. Bradycardia, heart block.
      4. CNS depression, sense of fatigue.
      5. Impotence.
    • III. Calcium Channel Blockers
      There are two main types of voltage-dependent Ca2+ channels:-
      1. L-type (Long-lasting) with slow inactivation and high conductivity.
      2. T-type (Transient) with fast inactivation and low conductivity.
      Ca2+ channel blockers act on α1 subunit of L-type channel that is located in conductive tissues (SAN & AVN) cardiac myocytes and vascular smooth muscle including coronaries.
    • Classification, Actions, Uses and Adverse Reactions of Calcium Channel Blockers
    • Calcium Channel Blockers for Hypertension
      Mechanism of Action
      Peripheral VD and ↓ TPR.
      Diuretic action secondary to ↑ renal blood flow.
      ↓ Aldosterone secretion.
      Advantages
      No metabolic side effects (no changes in glucose, lipid or uric acid levels).
      No affection of sexual activity.
      May improve renal function.
    • Indications :
      2nd Choice after diuretics in elderly hypertensives or in isolated systolic hypertension.
      2nd Choice after b blockers in hypertensives with coronary heart disease.
      Hypertension with peripheral vascular disease (PVD).
      Hypertension with renal impairment.
      Preparations and Dosage:
      Amlodipine 5 mg once daily.
      Verapamil 240 mg SR once daily.
    • IV. Angiotensin-Converting Enzyme (ACE) Inhibitors
      Angiotensinogen
      Renin
      Bradykinin
      Angiotensin I
      ACE
      Angiotensin II
      Inactive peptide
      AT2 Receptors
      • Protective VD.
      • Anti-proliferative.
      AT1 Receptors
      • Direct VC.
      •  Sympathetic (central + peripheral).
      • ↑ Aldosterone (Na+ retention).
      • ↑ ADH (water retention).
      •  Proliferation of myocytes in heart and vessel wall.
      AT4 Receptors?
      • Prothrombotic:
      ↑ Fibrinogen.
      ↑ Plasminogen activator inhibitor I (PAI1)
    • Mechanism of Action of ACEIs: ACEIs have dual vasodilator action by:
      1. ↓ Angiotensin II formation which mediates most of its effects through activation of AT1 receptors (inhibits vasospasm, salt & water retention & cardiac & vascular remodeling induced by angiotensin II).
      ↓ Activity of angiotensin II at AT2 receptors -> minimizes vasodilator effect of ACEIs (a disadvantage compared to ARBs).
      ↓ Activity of angiotensin II at AT4 receptors -> ↓its prothrombotic effect mediated by ↑ fibrinogen & PAI1 (an advantage over ARBs).
      2. ↑ Bradykinin through inhibition of its deactivation -> direct VD & release of potent vasodilator PGs and NO from vascular endothelium.
    • Therapeutic Uses of ACEIs
      I. Cardiovascular Uses
      ACE inhibitors have unique effects in preventing and treating cardiovascular diseases. They act on sequential events from risk factors to left ventricular failure.
    • The main cardiovascular indications of ACEIs are:
      Major risk factors
      1. Hypertension: ↓ BP, } Major risk factors
      ↓ LV hypertrophy
      2. Ischemic heart disease: inhibits atherogenesis and thrombogenesis.
      3. Myocardial infarction:
      Early administration during acute attacks prevents sudden death by preventing arrhythmia induced by hypokalemia and sympathetic overactivity.
      Decrease postinfarction remodeling caused by aldosterone and prevent heart failure.
      4. Heart failure: used in all stages of heart failure.
      Major risk factors
    • II. Nephropathy (diabetic or nondiabetic)
      ACEIs decrease intraglomerular pressure, progressive glomerulosclerosis, and proteinuria and delay the onset of renal failure.
    • ADVERSE REACTIONS
      Related to
      ↑ Bradykinin
      Related to
      ↓ Angiotensin II
      Related to
      High DoseCaptopril (immune-base)
      • Acute angioedema (early)
      • Chronic dry cough (late).
      Hypotension
      Renal impairment
      Hyperkalemia (↓ aldosterone)
      • Skin allergy
      • Neutropenia
      • Proteinuria
      • Loss of taste.
    • 1. Cough
      Common side effect which may disappear after 4 months. Addition of low dose of nifedipine may decrease cough. If not, shift to angiotensin receptor blockers (ARBs).
      2. Angioedema
      Rare but may be fatal. Epinephrine and intubation may be needed.
      3. Hypotension and reversible renal failure
      More common in high renin states such as in patients on diuretics, or those with heart failure or renal artery stenosis.
      4. Hyperkalemia
      Occurs with co-administration of b blockers, aldosterone antagonist or renal impairment.
    • Class I
      Captopril (SH)
      Class II
      Enalapril - Perindopril
      Ramipril - Fosinopril
      Class III
      Lisinopril
      Classification of ACEIs
    • Class I (Captopril) :
      Not a prodrug.
      Rapid onset & short duration (t½ 4-6 h), can be given sublingually in severe hypertension
      ↓ Nitrate tolerance (due to its SH group).
      Class II (Enalapril - Perindopril - Ramipril - Fosinopril):
      Prodrugs (activated first in liver).
      Slow onset & long duration (given once/day).
      Have carboxyl group not SH group with absence of immune base side effects of captopril.
      Fosinopril has phosphoryl group instead of carboxyl group with dual route of excretion (hepatic & renal) -> no dose adjustment in renal failure.
    • Classification (contin)
      Class III (lisinopril) :
      Not a prodrug.
      Long duration.
      Water soluble, not metabolized in liver and excreted unchanged by the kidney -> given in liver disease.
    • ACE Inhibitors in Hypertension
      Mechanism of Action
      1. Vasodilation due to ↓ angiotensin II & ↑ vasodilator BK, PGs & NO.
      2. Anti-adrenergic effect by blocking central & peripheral adrenergic activity of angiotensin II (thus ACEIs decrease BP without reflex tachycardia).
      3. Inhibition of aldosterone -> Na+ loss.
    • Advantages
      1. ↓ Cardiovascular mortality and morbidity.
      2. Protect renal function especially in diabetics.
      3. No metabolic side effects (no effect on glucose, lipid or uric acid).
      4. May improve glucose intolerance in insulin resistance.
      5. No changes in heart rate.
      Indications
      1. Diabetic hypertensives.
      2. Hypertension with nephropathy in diabetics or nondiabetics.
      3. Hypertension in HF or after myocardial infarction.
    • V. Angiotensin II Receptor Blockers (ARBs)(Losartan - Valsartan - Telmisartan)
      They block angiotensin II receptor type I (AT1) responsible for most of the damaging effects of angiotensin II (see figure p. 179).
      Advantages of ARBs over ACEIs
      1. Antagonize AG II formed by both ACE & non-ACE pathway (e.g. chymase).
      2. They are able to avoid hormonal "escape" (↑ renin & angiotensin II) which may occur during prolonged administration of ACEIs.
      3. They block the hypersensitivity of AT1 receptor caused by insulin or LDL.
      4. Blocking AT1 receptor directs angiotensin II to AT2 receptor which has vasodilator action and antiproliferative effect.
      5. No production of bradykinin which may be responsible for angioedema and cough seen with ACEIs.
    • Disadvantages of ARBs
      1. Lack of protective effect of bradykinin due to NO & PGs formation.
      2. Activation of AT4 receptor responsible for prothrombotic effect with increased fibrinogen, plasminogen activator inhibitor I.
    • VI. Direct VasodilatorsHydralazine
      Mechanism of Action
      It is an arteriolar vasodilator that may act as a K+ channel opener with hyperpolarization of vascular membrane which prevents Ca2+ influx into the wall of blood vessels.
      Pharmacokinetics
      It is rapidly absorbed from the gut.
      It is metabolized in the liver by acetylation. Fast acetylators need large dose, while slow acetylators may develop lupus syndrome.
      It is excreted by the kidney and the dose should be reduced in renal disease.
    • Indications :-
      1. Hypertension
      a. IV hydralazine is the drug of choice in severe hypertension with pregnancy.
      b. The chronic use of hydralazine in hypertension is associated with rapid tolerance due to reflex activation of the sympathetic and renin-angiotensin systems resulting in salt retention and reflex tachycardia. So it is often used with diuretics and b blockers.
      2. Congestive Heart Failure
      It is not used alone but usually combined with nitrates.
      It potentiates the effect of nitrates by reducing afterload and by reducing nitrate tolerance by decreasing free radical formation.
    • 3. Mitral Regurge
      Hydralazine, by decreasing peripheral resistance, increases forward stroke volume and decreases regurgitant volume.
      Adverse Effects
      Salt retention and edema.
      Reflex tachycardia.
      Lupus syndrome.
    • Sodium Nitroprusside
      Mechanism of Action
      It is a donor of nitric oxide (NO) that increases the level of cGMP which induces vasodilation by inhibiting Ca2+ influx into the wall of blood vessels.
      Pharmacological Properties
      It has a potent direct vasodilator (arteriolar and venular) effect decreasing both preload and afterload.
      It has an immediate effect and very short duration of action (2 minutes).
      It is converted in the body into cyanomethemoglobin and free cyanide which is metabolized into thiocyanate in liver and excreted by the kidney.
    • Indications :-
      1. Hypertensive Emergencies
      It is useful in most hypertensive emergencies as hypertensive encephalopathy, severe hypertension with acute HF and dissecting aortic aneurysm.
      2. Severe Acute Heart Failure
      It is useful in severe acute HF especially with mitral and aortic regurgitation provided the arterial pressure is reasonable.
      It may be used in acute HF complicating myocardial infarction, cardiac surgery or acute exacerbation of chronic HF.
      Nitroprusside is now replaced by safer drugs as nitroglycerin or milrinone (an inotropodilator).
    • Toxicity
      1. Cyanide Toxicity
      Occurs especially when it is given at high doses for long periods, particularly in liver and renal diseases which limit cyanide clearance.
      It varies from mild abdominal pain & vomiting to neurological symptoms as headache, confusion and convulsions up to unexplained death.
      Treatment
      Sodium nitrate 3% solution 2.5 ml/min for 5 min, followed by sodium thiosulfate 12.5 g in solution of 5% D/W over 10 minutes.
      Overdose may cause severe hypotension and myocardial ischemia.
      Dosage: 0.5-10 mg/kg/min IV infusion.
    • Precautions :-
      a. Infusion rate needs careful titration against BP, which must be continuously monitored to avoid excessive hypotension (potentially fatal).
      b. Avoid extravasation.
      c. Solution in normal saline should be freshly prepared and then protected from light during infusion.
      d. Solution should be discarded when it is 4 hours old or if it is discolored.
    • VII. Sympatholytics
      They include centrally-acting drugs and a1-adrenoceptor blockers.
      Mechanism of Action of Centrally-Acting Drugs
      Relmenidine
      Moxonidine
      Clonidine
      Methyldopa
      Imidazoline Receptor
      Rostral ventrolateral medulla (RVLM)
      α2 Receptor
      Nucleus tractus solitarius (NTS)



      Salivary gland
      (Dryness)
      Locus ceruleus
      (Sedation)
      Central Sympathetic Discharge
    • Sympatholytics used in Hypertension
    • Hypertension in the elderly
      Benefit from antihypetensive therapy is evident up to at least 80 years of age.
      The thresholds for treatment are diastolic pressure averaging 90 mmHg and systolic pressure averaging 160 mmHg.
      A low dose of a thiazide is the drug of first choice, with addition of another antihypertensive when necessary.
    • Isolated Systolic Hypertension
      ISH (systolic > or = 160, diastolic <90mmHg, should be lowered, even if diastolic hypertension is absent.
      Treatment with a low dose of a thiazide, with addition of a B-blocker when necessary is effective.
      A long-acting dihydropyridine CCB is given when a thiazide is contraindicated or not tolerated.
      Patients with severe postural Hypotension should not receive BP lowering drugs.
    • Hypertension in Diabetes
      The aim should be to maintain SBP<130 and DBP<80 mmHg.
      HTN is common in type 2 DM and treatment of HTN prevents macrovascular and microvascular complications.
      In type I DM, HTN usually indicates diabetic nephropathy.
      An ACEI or ARB may have a specific role in the management of diabetic nephropathy.
      In type 2, an ACEI or ARB can delay progression of microalbuminuria to nephropathy.
    • Hypertension in renal disease
      The thresholds for treatment in are diastolic pressure averaging 90 mmHg and systolic pressure averaging 140 mmHg.
      Optimal BP is a SBP <130 and a DBP<80 mmHg if proteinuria exeeds 1 g in 24 h.
      Thiazides may be ineffective and high doses of loop diuretics may be required.
      Specific cautions apply to the use of ACEI in renal impairment, but ACEIs may be effective.
      DHP CCBs may be added.
    • Hypertension in Pregnancy
      High BP in pregnancy may usually be due to pre-existing essential HTN or to pre-eclampsia.
      Methyldopa is safe in pregnancy.
      B-blockers are effective and safe in the third trimester.
      Modified release preparations of nifedipine are also used in HTN in pregnancy.
      IV labetalol or hydralazine can be used to control hypertensive crisis.
      Magnesium sulphate is the drug of choice to prevent seizures in pre-eclampsia and eclampsia
    • Hypertensive Crisis
      Hypertensive crisis is defined as severe elevation in BP usually a systolic BP exceeding 220 mmHg and/or a diastolic BP greater than 120 mmHg.
      It includes hypertensive emergencies and hypertensive urgencies.
      Hypertensive Urgencies
      It is severe elevation of BP in absence of progressive target-organ damage.
      Immediate reduction in BP is not indicated and can be managed as outpatient case using combination of oral antihypertensives.
      Hypertensive Emergencies
      It is severe elevation in BP with acute progressive target-organ damage.
      It represents an acute life-threatening situation which requires ICU admission for immediate controlled reduction in BP using IV drug therapy to avoid death or irreversible organ damage.
    • Clinical Conditions Associated with HypertensiveEmergencies & their Drug Therapy :-
      1. Malignant Hypertension
      It is associated with bilateral retinal hemorrhage and/or exudates with or without papilledema.
      Fenoldopam D1 agonist is the preferred drug, as it ↑ renal blood flow.
      Other drugs: labetalol, enalaprilat.
      2. Hypertensive Encephalopathy
      It is associated with neurological manifestations as headache, vomiting, visual disturbance, confusion or convulsions.
      BP should be reduced gradually not to normal level to avoid brain ischemia.
      Preferred drugs: labetalol, nitroprusside.
      Nimodipine is used in subarachnoid hemorrhage -> ↓ cerebral vasospasm.
    • 3. Acute Coronary Syndrome (unstable angina & myocardial infarction)
      Nitroglycerin, esmolol are preferred drugs.
      Nitroprusside is preserved for resistant cases as it may ↓ coronary BF.
      4. Acute Left Ventricular Failure
      Enalaprilat, nitroglycerin and nitroprusside are preferred.
      b Blockers are avoided.
      5. Dissecting Aortic Aneurysm
      Drugs used: esmolol and nitroprusside.
    • 6. Excessive Circulating Catecholamines
      Occurs in pheochromocytoma, clonidine withdrawal and food interaction with MAO inhibitors.
      Drugs used: phentolamine (plus b blockers) or labetalol (without b Bs)
      7. Eclampsia
      Hydralazine, nitroglycerin, labetalol may be used.
      8. Perioperative
      Includes severe hypertension in patient requiring immediate surgery or postoperative hypertension (↑ risk of myocardial infarction).
      Drugs used: nitroglycerin, esmolol, labetalol, nitroprusside.
    • Parenteral Agents for Hypertensive Emergencies