Hypertension

HYPERTENSION

Hypertension is the most common cardiovascular disease. It is defined as sustained high Blood Pressure >140/90mmHg. It is associated with an increase in peripheral resistance.

Etiology of Hypertension

Essential Hypertension (90%): - No specific cause. Family history. Environmental factors:

1- Stress. 2- Obesity. 3- High Sodium diet. 4- Smoking.

Regulation of Blood Pressure (B.P)

B.P is proportional to product of Cardiac output (C.O) and Peripheral vascular resistance (PVR). Physiologically, B.P is maintained by moment-to-moment regulation of C.O and PVR exerted at 4 anatomic sites: - Arterioles, Post-capillary venules, heart and kidney. Regulation of B.P occurs through:

A- Baroreceptors and Sympathetic nervous system: - Carotid baroreceptors (stimulated by stretch of blood vessel

wall by internal B.P) normally send inhibitory impulses to vasomotor centre (VMC) in the medulla.

- A fall in B.P causes carotid baroreceptors to send fewer inhibitory impulses to VMC increasing sympathetic activity to the heart (increased C.O) as well as arteriolar vasoconstriction (increased PVR) and vasoconstriction of the venules (increased venous return), thus leading to restoration of normal B.P.

This baroreflex acts in response to: - Changes in posture. - Decrease in PVR secondary to vasoconstrictors. - Decreased intravascular volume due to low sodium diet, diuretics, blood

loss and C.H.F. B- Renin-Angiotensin-Aldosterone System (RAAS):

By controlling blood volume, kidney is responsible for long term B.P control. This occurs through:

1- Decreased Renal perfusion pressure resulting in increased Renal salt and water reabsorption.

2- Decreased pressure in renal arterioles leading to increased Renin. This results in formation of Angiotensin II leading to vasoconstriction, increased NE and secretion of Aldosterone which results in increased B.P.

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In hypertensive patients, Baroreceptors and RAAS are set at a higher level of B.P and antihypertensive drugs act by interfering with these mechanisms. Aim of Antihypertensive therapy

Chronic hypertension can lead to organ damage as C.H.F, Myocardial infarction, Renal damage and Cerebrovascular accidents. The aim of therapy is to prevent target organ damage by keeping B.P below 140/90mmHg.

Classification of Antihypertensive Drugs

I- Diuretics. II- Sympathomimetics:

1- Central acting: - Clonidine, Moxinidine, Methyldopa. 2- Beta-Adrenergic Blockers: - Propranolol, Atenolol. 3- Alpha-Adrenergic Blockers: - Prazocin, Doxazocin. 4- Adrenergic Neuronal Blockers: - Reserpine.

III- Angiotensin-Converting Enzyme Inhibitors (ACEIs). IV- Angiotensin II Receptor Blockers (ARBs). V- Calcium Channel Blockers (CCBs). VI- Vasodilators:

1- Arterial: - Hydralazine, Minoxidil, Fenoldopam, Diazoxide. 2- Mixed: - Sodium nitroprusside.

Clonidine VMC (-) Beta-Blockers Methydopa (-) sympathetic outflow Monoxidine Alpha-Blockers (-) alpha Resetting of Baroreceptors CCBs (-) Ca++ Heart; decreased C.O. Vasodilators Blood Block Renin vessels AT-II Renin- VC Angiotensin Aldosterone system increase in B.V. (-) (-) Diuretics ACEIs Fig: Control of B.P and sites of action of Antihypertensive Drugs.


DIURETICS

Diuretics decrease B.P by depleting body sodium stores and reducing blood volume.

Used as monotherapy in mild or moderate hypertension. Combined with sympatholytics or vasodilators in severe hypertension (decrease

salt and water retention induced by these agents). Thiazides are the most frequently used class of diuretics:

- Effective at low doses (Hydrochlorthiazide 12.5mg daily). - Usually combined with K+ sparing diuretics. - If another drug is required, ACEIs and ARBs are used (i.e.

decrease K+ loss by Thiazides). Toxicity of Diuretics:

1) Hypokalemia. 2) Hypomagnesemia. 3) Increased serum lipid and impair glucose tolerance increasing the risk of ischemic

heart disease. 4) Hyperurecemia. 5) Sexual impairment.

BETA-ADRENOCEPTOR BLOCKERS

Beta-blockers provide effective therapy for all grades of hypertension. They do not produce postural hypotension. They do not produce salt and water retention. Used in combination with Vasodilators in cases of severe hypertension to prevent

reflex tachycardia that occurs with these drugs. Preparations and Dosage:

1- Propranolol: - Non-selective and lipophilic. - 20mg Tabs twice daily; increased rapidly until optimal B.P

control. 2- Atenolol: - Selective and hydrophilic.

- 50-100mg Tabs once daily. 3- Carvedilol: - Vasodilatory lipophilic Beta-blocker with additional Alpha-1 blocking effect; 6.25mg twice daily orally. 4- Labetalol: - Alpha-1 and Beta adrenergic receptor blocker used I.V in

hypertensive emergency.


ANGIOTENSIN-CONVERTING ENZYME INHIBITORS (ACEIs) Classification according to Chemical Structure SH group Dicarboxyl group Phosphorus group - Captopril - Enalapril - Fosinopril (Prototype) - Lisinopril - Ramipril All listed members are pro-drugs except Captopril and Lisinopril. Mechanism of action: - ACEIs inhibit angiotensin-converting enzyme which is responsible for the formation of angiotensin II and breakdown of bradykinin. This results in:

1- Reduction of plasma angiotensin II causing arteriolar and venular vasodilatation. 2- Reduction of aldosterone leading to salt and water excretion with K+ retention. 3- Preservation of kinins which are vasodilators. 4- ACEIs inhibit Angiotensin II formation in tissues (heart and blood vessels)

preventing myocardial hypertrophy and remodeling following myocardial infarction.

Mechanism of action of ACEIs Bradykinin Angiotensin I ACE Kininase (-) ACEIs (-) ACE Inactive metabolites Angiotensin II Angiotensin II receptor blockers (-) AT-II receptors Increased Aldosterone Vasoconstriction Increased NE


Pharmacological actions:

I- Vascular effects: 1- Lower B.P mainly by lowering peripheral vascular resistance. 2- Prominent renal vasodilator effect leading to Natriuresis. 3- Induce minimal change in C.O or H.R (do no induce reflex tachycardia

due to blunting of sympathetic reflex) [inhibit Angiotensin II induced NE release].

4- No postural hypotension. II- Cardiac effects:

1) Arteriolar dilatation leading to decreased afterload and improve cardiac output (C.O) resulting in decreased fatigue.

2) Reduced renovascular resistance (Decreased renal vasoconstriction of Angiotensin II) leading to increased renal blood flow.

3) Reduced Aldosterone secretion. v Increased Renal blood flow & Decreased Aldosterone secretion produce

Natriuresis. 4) Venodilatation leading to decreased preload. v Natriuresis & Decreased preload produce Decreased filling pressures resulting in

improved pulmonary and venous congestion. 5) Reversal of ventricular remodeling through:

Reduced preload and after-load. Preventing the trophic effects of Angiotensin II on monocytes. Attenuating Aldosterone-induced cardiac fibrosis.

III- Cerebral and Coronary blood flow is well maintained. Pharmacokinetics of ACEIs: ACEIs are absorbed rapidly orally, metabolized in the liver and excreted by the kidney. Captopril: - Bioavailability 75%; reduced by food. It is given one hour before meals.

- t1/2 is 11 hours. Enalapril: - Pro-drug; hydrolyzed in liver into active Enalaprilat.

- Bioavailability 60%; not reduced by food. t1/2 is 11 hours. Ramipril: - Rapidly absorbed and metabolized to Ramiprilat.

- Extensive tissue distribution. - Long duration of action.

Fosinopril: - Renal as well as biliary excretion. Advantages of ACEIs over other Anti-hypertensives:

1) No change in heart rate. 2) No metabolic side effects:

Do not alter blood uric acid or cholesterol levels. Improve glucose tolerance and diabetic nephropathy.

3) Regression of left ventricular hypertrophy.


Therapeutic uses of ACEIs:

1- Hypertension: Essential hypertension: First line drugs as monotherapy in mild to moderate

hypertension or combined with diuretics, calcium channel blockers or Beta-blockers.

Hypertension with diabetes (1st choice; no metabolic adverse effects). Hypertension with C.H.F (Combined with a diuretic). High Renin hypertension e.g. unilateral renal artery stenosis.

2- Congestive Heart failure: Delay progress of heart failure. Improve quality of life.

3- Following myocardial infarction: Start therapy immediately after infarction. Preserve left ventricular function and decreases remodeling.

Preparations and Dosage of ACEIs

1. Captopril: - 25mg Tab. Start with 6.25mg twice daily given 1 hour before meal.

2. Enalapril: - 2.5mg Tab. Once daily. 3. Enalaprilat: - 0.625 1.25mg I.V over 5 minutes. 4. Lisinopril: - 2.5 5mg Tab. Once daily. 5. Ramipril: - Start with oral dose 1.25mg once daily.

Adverse effects and Contraindications:

1- 1st dose hypotension (Start with small dose). 2- Skin rash. 3- Persistent dry cough (Raised bradykinin and increased PGs); may be relieved by

NSAIDS. 4- Temporary loss of taste. 5- Proteinuria and Nephrotic syndrome in patients with renal disease. 6- Neutropenia (Rare but Serious). 7- Hyperkalemia occurs in patients with renal insufficiency, or those taking Beta-

blockers and/or Potassium-sparing diuretics. 8- Angioedema (Raised bradykinin and auto-antibodies). 9- Fetopathic (Hypotension, Anuria and renal failure). Therefore ACEIs are

contraindicated in pregnancy. 10- Acute renal failure. Contraindicated in Bilateral renal artery stenosis.

Drug Interactions with ACEIs

K+ supplements and K+ sparing diuretics produce Hyperkalemia. NSAIDs results in decreased Antihypertensive effects of ACEIs.


ANGIOTENSIN RECEPTOR BLOCKERS (ARBs)

They are competitive blockers of Angiotensin II receptor Type 1 (AT1). Orally active; Bioavailability Verapamil > Diltiazem. The greater degree of vasodilatation seen with Dihydropyridines results in increase in sympathetic tone which produces increased H.R and C.O. Coronary vasodilatation leading to increased myocardial Oxygen supply

producing Anti-anginal effect.


II- Cardiac effect: a) Effect on myocardial contractility:

All CCBs produce a negative inotropic effect: Verapamil > Diltiazem.

Dihydropyridines relax vascular smooth muscles at lower concentrations than those required to induce negative inotropism. This results in reflex sympathetic activation overcoming their negative inotropic effect.

Decrease contractility and Vasodilatation leading to decreased B.P resulting in decreased work done by the heart thus producing Anti-hypertensive and Anti-anginal effects.

b) Effect on AV node conduction: Verapamil and Diltiazem decrease H.R and AV conduction. Nifedipine has no effect on AV conduction. Verapamil and Diltiazem slows AV node conduction thereby protects

ventricles from rapid atrial rate in supraventricular arrhythmia producing Anti-arrhythmic effect.

Pharmacokinetics of CCB:

1- Nearly completely absorbed orally (effect appears within 30-60 minutes). 2- First pass metabolism resulting in decreased bioavailabilty. 3- 70-98% bound to plasma proteins. 4- Elimination half-life is widely variable (1.5 50 hrs). 5- Amlodipine is slowly absorbed with long duration of action (t1/2 = 35-50 hrs)

produces no fluctuations in blood level resulting in smooth hypotensive effect producing less reflex tachycardia.

6- Nimodipine is highly lipid soluble, effective in cerebral vasospasm following sub-arachinoid hemorrhage.

Therapeutic uses of CCB:

1- Anti-angina (All types of Angina). 2- Anti-arrhythmic in Supra-ventricular arrhythmia:

1st Choice in prophylaxis and 2nd Choice after Adenosine in treatment of Supra-ventricular tachycardia.

Reduce ventricular rate in atrial flutter and atrial fibrillation. 3- Anti-hypertensive:

All are equally effective when used alone in mild to moderate hypertension.

Effective in Low Renin Hypertension (with NO heart failure and no volume depletion).

CCB can be used parenterally in emergency. 4- Hypertrophic cardiomyopathy. 5- Migraine prophylaxis. 6- Raynauds disease. 7- Premature labor (Relaxation of myometrium thereby delay labor).


Preparation and Dosage of CCB: 1- Nifedipine:

- Available for oral and I.V use. - Oral capsule 10mg/8hrs and Slow release tablets 30mg.

2- Amilodipine: - Oral tablets 5 10mg once daily. 3- Verapamil:

- Tablets 80mg/8hrs. - Parenterally 5mg/2ml by slow I.V.I.

4- Diltiazem: - 30mg tablet/6hrs. - 5mg/ml by slow I.V.I.

Side effects of CCB:

1- Dizziness, headache, flushing. 2- Hypotension. 3- Bradycardia, heart block, heart failure with Verapamil (Verapamil is

contraindicated in heart block and heart failure). 4- Reflex tachycardia with Nifedipine. 5- Peripheral oedema (due to vasodilatation and increased hydrostatic pressure). 6- Constipation. 7- CCB + Beta-blockers produce Heart block and heart failure.

VASODILATORS (VDs) Oral Parenteral Long term outpatient For hypertensive emergencies Therapy of Hypertension. Sodium nitroprusside. - Hydralazine. Diazoxide. - Monoxidil. Fenoldopam.

1- Hydralazine: Dilates arterioles and not veins. Molecular mechanism not known. Used in severe hypertension. Cannot be used as monotherapy due to development of tachyphylaxis (loss

of anti-hypertensive effect) due to: 1) Increased Heart rate leading to increased cardiac output (has to

be combined with Beta-blockers). 2) Fluid retention (combined with a diuretic).

Side effects of Hydralazine: Vasodilatation resulting in: - Headache, flushing, tachycardia, angina. Immunological lupus syndrome.


2- Minoxidil: Arteriolar dilator resulting in headache, flushing, palpitation, angina. Opens K+ channel in smooth muscle membrane. Alternative to Hydralazine when maximal doses of Hydralazine are not effective. Used in combination with diuretics and Beta-blockers to avoid tachyphylaxis. Topical Minoxidil is used as a hair growth stimulant in alopecia.

3- Sodium nitroprusside: Powerful vasodilator of both arterial and venous vessels. Activates guanyl cyclase resulting in increased cAMP leading to vasodilatation. Given by I.V infusion (0.5 10ug/kg/min) producing decreased B.P. Sensitive to light: Solution is freshly prepared and covered with opaque foil. Rapidly metabolized by uptake into RBCs with liberation of cyanide. Toxicity: Accumulation of Cyanide: - Metabolic acidosis, excessive hypotension, arrhythmia, methemoglobinemia. Treatment of Cyanide toxicity: Hydroxycobolamine (Vit. B12) and Sodium thiosulphate. 4- Diazoxide: Opens K+ channel and stabilizes membrane potential. Similar to Thiazides but has no diuretic effect. Given by I.V infusion 15mg/min until B.P is controlled.

Side effects: - Vasodilatation resulting in Headache, flushing, palpitation, hyperglycemia

(inhibits Insulin release).

5- Fenoldopam: Arteriolar dilator for hypertensive emergency. Dopamine D1 agonist.

Side effects: - Vasodilatation resulting Headache, flushing. - Hypokalemia.

CHOICE OF ANTI-HYPERTENSIVE DRUGS Hypertensive emergencies:

- Frusemide I.V. - Diazoxide I.V. - Sodium nitroprusside (I.V infusion). - Labeterol I.V.


Hypertension and Heart failure:

- Drugs of choice: ACEIs, Diuretics. v Beta-blockers and CCBs are contraindicated.

Hypertension in Pregnancy:

- Methydopa. - Beta-blocker: - Atenolol. - Hydralazine.

v ACEIs (teratogenic) and Diuretics (volume depletion) are contraindicated. Hypertension and Peripheral Vascular Disease:

- Drugs of choice: CCBs, Selective Alpha-1 blockers. v Beta-blockers are contraindicated; produce vasoconstriction.

Hypertension and Bronchial Asthma:

- Drugs of Choice: - CCBs, Diuretics. v Beta-blockers are contraindicated; produce bronchospasm.

Hypertension and Ischemic Heart Disease:

- Drugs of choice: - CCBs (All types of Angina). - Beta-blockers (except in variant angina).

Hypertension and Diabetes:

- Drugs of choice: - ACEIs (favorable effect on sugar and lipid). - Selective Alpha-1 blockers.

v Beta-blockers are contraindicated; produce intolerance.


Hypertension

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