therapy of hypertension by dr. mohamed abd almoneim attia

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Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

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Page 1: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Therapy of hypertension

ByDr. Mohamed Abd Almoneim Attia

Page 2: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Calcium channel blockers (CCBs) These are drugs that block voltage-gated Ca2+ channels. Classification of CCBs according to therapeutic effect: CCB with mainly cardiac effects: verapamil, diltiazem.CCB with mainly vascular effects: nifedipine, amlodipine, isradipine.CCB with mainly tissue protection: flunarizin, cinnarizine N.B : Voltage-dependent Ca2+ channels: they are of 3 main types: L-type (Large in conductance or Long lasting).T-type (Transient in duration).N-type (Neuronal in distribution).L-type channel is the dominant type in cardiac and vascular sm ms.They open in response to cell depolarization and could be blocked by calcium channel

blockers.Calcium channel blockers block the L-type more than other types.

Page 3: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Pharmacokinetics: Oral absorption is nearly complete. Plasma protein binding is 70-98% ....... Metabolism: verapamil and diltiazem are

metabolized into active metabolites. In older patients and in patients with liver

cirrhosis the dose should be decreased.

Pharmacological effects:

Page 4: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Verapamil Diltiazem Nifedipine

+++↓↓↓↓↓

++↓↓↓

--↑ (reflex)

Heart:–ve inotropic effectA-V conductionHR

+↓

++↓

+++↓↓↓

Blood vessels:Coronary and arterial dilatationBP

Page 5: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Other effects: 1-Smooth muscles: they relax bronchial, GIT, and

uterine smooth ms.2-Platelets: they ↓ platelet aggregation.3-Insulin release: verapamil ↓ insulin release (in

high dose).4-CNS: they ↓ seizure (convulsions) activity.

Page 6: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Therapeutic uses:A. Cardio-selective CCBs (verapamil and diltiazem):

1-Ischemic heart disease: see IHDThey ↓ myocardial contractility and myocardial O2 demand.

They ↓ coronary vascular resistance and increase coronary blood flow.

They dilate epicardial coronary vessels.They improve myocardial relaxation and ↓ myocardial cell necrosis.

N.B.Although nifedipine is coronary dilator, it has some

disadvantages in angina: It may cause hypotension and reflex tachycardia.It may cause “steal phenomenon” .

Page 7: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

2-Cardiac arrhythmias: supraventricular tachycardia (SVT):

Because they ↓ SAN activity and slow A-V conduction.

N.B.Nifedipine is contraindicated because it cause

hypotension and reflex tachycardia.

Page 8: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

3-Hypertrophic obstructive cardiomyopathy (IHSS):In hypertrophic obstructive cardiomyopathy, the wall of

the left ventricle and interventricular septum is much thickened leading to narrowing of the aortic outlet and obstruction of blood flow. This obstruction is increased by increasing contractility while decreasing contractility leads to decrease resistance to blood flow through the aortic outlet.

N.B.Nifedipine is contraindicated because it produces

reflex tachycardia → worsening of the outflow obstruction.

Page 9: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

4-Arterial hypertension:They cause VD due to ↓ Ca2+ influx in the vascular sm ms.They ↓ myocardial contractility and COP.They ↓ platelet aggregation.

B. Vasculo-selective CCBs (Nifedipine and amlodipine): 1-Arterial hypertension.2-Senile cerebral ischemia (nimodipine).3-Peripheral vascular disease: to improve peripheral

microcirculation.4-Chronic renal failure: to minimize renal ischemia.5-Re-perfusion injury: to minimize tissue damage.6-Prophylaxis of migraine: by unknown mechanism.

Page 10: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Adverse effects:1-Verapamil and diltiazem:*Bradycardia and heart block.*Worsening of CHF (due to their –ve inotropic

effect).*↓ insulin release and worsening of DM.*Constipation and reversible hepatotoxicity.*Ankle edema (less common than with

nifedipine).

Page 11: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

2-Nifedipine:*Hypotension and reflex tachycardia.*Steal phenomenon and aggravation of angina.*Gingival hyperplasia. *Ankle edema (due to VD).How to treat ankle edema if occurred from CCBs?Minimize sodium intake.Avoid prolonged standing.Mild diuretics.Stop CCBs if the above measures failed.

Page 12: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Contraindications and precautions: 1-Verapamil:Heart failure.Bradycardia, heart block, or sick sinus syndrome (SSS).With β-blockers: because both β-blockers and verapamil

have –ve inotropic and chronotropic effects, this will cause severe cardiac depression (nifedipine is the drug of choice if β-blockers are used with CCBs because it doesn't cause bradycardia).

With digitalis: because digitalis also ↓ A-V conduction and

HR.

Page 13: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

2-Nifedipine:Severe heart failure. Hypotension.Hypertrophic obstructive cardiomyopathy (IHSS)Unstable angina (for fear of reflex tachycardia

and steal phenomenon).

Page 14: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

RENNIN ANGIOTENSIN ALDESTERON SYSTEM• RENIN: It is a proteolytic enzyme secreted by

the kidney into the blood stream.Stimuli that increase renin secretion: Sodium depletion, diuretics, hypotension, hemorrhage, upright posture, dehydration, constriction of renal artery, heart failure and Cirrhosis

Page 15: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Actions of Angiotensins• Angiotensin I (precursor of angiotensin II): It has no pharmacological

action.• Angiotensin II: It acts on two receptors; AT1 and AT2 receptors

(1) Its action on AT1 receptor produces the following:

CVS: • Arteriolar constriction leading to increased systolic and diastolic blood

pressure (40 times as active as norepinephrine).• Angiotensin II produces positive inotropic and chronotropic effects

which are primarily due to central and peripheral sympathetic stimulation.

Endocrine: • Increase secretion and synthesis of aldosterone which causes Na and

water retension.• Facilitate catecholamine synthesis and release.• Increase pituitary vasopressin and ACTH.

Page 16: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Renal:• Suppress renin release• V.C of renal efferent arterioles, increases proximal

tubular Na+ reabsorption C.N.S• Increase H2O intake and vasopressin secretion.• Stimulate central sympathetic discharge. (2)Its action on AT2

receptor produces the following:• Antiproliferation.• Apoptosis (normal cell death).• Vasodilatation and increase local bradykinin.

Page 17: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia
Page 18: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Stimulators of renin-Ang system: Renal ischemia of any cause.Hypovolemia and hypotension.β1 agonists.

Vasodilators.

Inhibitors of the renin-Ang system: Inhibitors of renin release: β-blockers, α-methyldopa,

clonidine.Inhibitors of plasma renin activity: aliskrine.Inhibitors of Ang-2 formation: angiotensin-converting

enzyme inhibitors (ACEIs)(pril)Blockers of AT receptors: saralasin, losartan, valsartan

Page 19: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Angiotensin-converting enzyme inhibitors (ACEIs): Classification:A-SH-Containing: Captopril ZofinoprilThe sulfhydryl group (-SH) present in captopril may be

responsible for the immunological side effects e.g. angioedema, taste changes, skin rash, leukopenia

B-Non SH-Containing: Enalapril Fosinopril Lisinopril Benazepril

Page 20: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Mechanism of action: They inhibit Ang-converting enzyme (ACE) leading to:

Inhibition of Ang-2 formation in the heart, blood vessels, and tissues.

Prevent degradation of bradykinin which is a potent VD.

Inhibition of aldosterone release.ACEIs have direct VD action to both arteries and

veins.

Page 21: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Pharmacological effects:

CVS: 1-They ↓ BP mainly by decreasing peripheral resistance but no reflex

tachycardia or changes in the COP can occur due to:Resetting of baroreceptors downwards.VenodilatationEnhanced parasympathetic activity.

2-They ↑ COP only in congestive heart failure (not in normal

conditions) due to reduction of systemic BP and peripheral VD. 3-They ↓ the left ventricular mass and wall thickening after myocardial

infarction because they prevent myocyte cell proliferation and collagen synthesis (i.e. prevent cardiac remodeling).

4-They maintain cerebral and coronary blood flow.

Page 22: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Kidney:They ↓ proteinuria in mild renal impairment

and diabetic patients.They ↑ RBF.

Cell growth and proliferation:They ↓ cell apoptosisThey ↓ cell proliferation and collagen synthesis.

Page 23: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Therapeutic uses:

1-Hypertension: 2-Congestive heart failure (CHF):

To ↓ arterial BP → ↓ afterload.To ↓ aldosterone → ↓ Na and H2O retention → ↓ preload.

To prevent myocardial hypertrophy and degeneration.

3-Post-infarction ventricular remodeling:To ↓ mass and wall thickness of the left ventricle through:

↓ arterial BP.↓ myocyte cell proliferation and collagen synthesis.↓ apoptosis.

4-Diabetic nephropathy and microalbuminuria:To ↓ apoptosis, cell proliferation, and collagen synthesis. 5-Possible other uses: Insulin resistance - Atherosclerosis - Rheumatoid arthritis

Page 24: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Side effects: CAPTOPRILC Cough and bronchospasm: inhibition of ACE leads to accumulation of bradykinin, which cause bronchial

irritation and constriction. Prevention: by administration of NSAIDs (e.g. aspirin) to ↓ bradykinin synthesis

A Angioedema (edema of the face and throat): due to accumulation of bradykinin or due to autoimmune reaction. It may be fatal.

P :Proteinuria in patients with compromised renal function.

T Taste changes: temporary loss of taste (ageusia and dysgeusia).

O Orthostatic (First dose) hypotension: especially in sodium depleted patients. Prevention: the first dose must be small and at bedtime then increase gradually. P Pregnancy: teratogenesis (fetal pulmonary hypoplasia and growth retardation)

R skin Rash

I Increased K+ (hyperkalemia).

L Leukopenia (neutropenia): especially in patients with impaired renal function.

Page 25: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Contraindications: 1-Hypotension. 2-Severe renal failure (serum creatinine > 3 mg/dl). 3-Bilateral renal artery stenosis or stenosis in a solitary kidney.In these conditions, the use of ACEIs is dangerous because they ↓ Ang-2 →

↓ VC of the efferent arterioles → ↓ GFR → aggravation of renal failure in both kidneys.

4-Pregnancy and lactation: they may cause fetal pulmonary hypoplasia and growth retardation.

5-Hyperkalemia.6-Neutropenia or thrombocytopenia.7-Severe anemia: as they may cause bone marrow depression.8-Immune problems: e.g. autoimmune diseases and with

immunosuppressive drugs.

Page 26: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Precautions: 1-Initial dose should be small and at bedtime to

avoid 1st dose hypotension.2-Frequent monitoring of kidney functions

(serum creatinine) one week after treatment and then every 3 months.

3-Frequent monitoring of serum K+.4-Avoid use with K+ sparing diuretics to avoid

severe hyperkalemia.5-Mention other contraindications…….

Page 27: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Angiotensin II receptor blockers (ARBs)(Losartan, valsartan, candesartan, eprosartan, telmisartan) They selectively block AT1 receptors.

They have no effect on bradykinin metabolism.They have the potential for more complete inhibition of

Ang-2 action compared with ACE inhibitors because there are non-ACE enzymes (cathepsin and chymase) that can convert Ang-1 into Ang-2.

The adverse effects and contraindications are similar to those described for ACE inhibitors but cough and angioedema are less common than with ACE inhibitors.

Page 28: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Vasodilators Classification 1-Arterio-dilators: e.g. nifedipine, hydralazine, minoxidil, diazoxide.They directly dilate arteries and reduce blood pressure (↓ afterload) so

they are used in systemic hypertension and congestive heart failure. 2-Venodilators: e.g. nitrates.They dilate veins (↓ preload) so they are used in acute pulmonary

edema. 3-Mixed dilators: sodium nitroprusside, prazosin, ACEIs, trimetaphan. They are used in congestive heart failure because they ↓ preload and

afterload.

Page 29: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

General considerations: They usually cause reflex sympathetic stimulation

(e.g. reflex tachycardia and ↑ plasma renin) so they can be combined with beta-blockers.

They usually cause salt and water retention so they should be combined with diuretics.

They don't cause CNS side effects or orthostatic hypotension.

They preserve renal and cerebral blood flow.

Page 30: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Hydralazine Mechanism: direct vasodilator for small arteries and arterioles. Therapeutic uses:

Severe systemic hypertension.Primary pulmonary hypertension.Hypertension in pregnancy (2nd choice after α-methyldopa).

Side effects:

Hypotension and reflex tachycardia. Salt and water retention.Headache, Anginal pain, Nausea, Dizziness (HAND).Systemic lupus erythematosis (SLE)-like syndrome in slow

acetylators.

Page 31: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Minoxidil Mechanism: direct arteriolodilator by opening K+ channels → hyperpolarization →

relaxation of the vascular sm ms. Therapeutic uses: Severe hypertension in combination therapy.Hypertension in (renal) patients.Topical minoxidil is used to stimulate hair growth in male baldness. Side effects: Hypotension and reflex tachycardia.Salt and water retention.Headache, Anginal pain, Nausea, Dizziness (HAND).Hypertrichosis= hirsutism (undesirable hair growth in the face and body).

Page 32: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Diazoxide Mechanism: direct arteriolodilator by opening K+ channels →

hyperpolarization → relaxation of the vascular sm ms. Therapeutic uses: Hypertensive emergencies e.g. hypertensive encephalopathy.

(rapid i.v. injection to avoid rapid and extensive binding with plasma proteins).

Hypoglycemia due to hyperinsulinism to decrease insulin secretion from the pancreatic β-cells through opening of its K+ channels.

Page 33: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Side effects: Hypotension and reflex tachycardia. Salt and water retention.Headache, Anginal pain, Nausea, Dizziness

(HAND).Hyperglycemia due to inhibition of insulin

release.Hyperuricemia.

Page 34: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Sodium nitroprusside Mechanism: It liberates nitric oxide (NO) → ↑ cGMP → ↓ Ca2+

entry in the vascular sm ms → dilatation of both arteries and veins.

It is rapidly metabolized in RBCs into cyanide then to thiocyanate

before excretion. Therapeutic uses: Hypertensive encephalopathy: It must be given by i.v. infusion .Congestive heart failure: to ↓ both preload (venodilatation) and

afterload (arteriolodilatation).

Page 35: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Side effects: Hypotension and reflex tachycardia.Headache, Anginal pain, Nausea, Dizziness (HAND).Prolonged therapy can lead to cyanide toxicity (death can occur

from metabolic acidosis and arrhythmia) or thiocyanate toxicity (delirium and psychosis).

►Precautions: Avoid exposure to light because the drug is sensitive to light.Stop infusion gradually to avoid rebound hypertension.Too much infusion may lead to cyanide toxicity.In liver disease cyanide ions are not converted into thiocyanate and

become more toxic.

Page 36: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Hypertensive emergencies:Defined as diastolic blood pressure more than 130 mmHg associated with progressive end organ damage e.g papilledema , hypertensive encephalopathy, pulmonary edema or acute renal failure.

The patient should be hospitalized for rapid but (careful and controlled) reduction of blood pressure.

Avoid excessive rapid lowering of blood pressure since it can result in stroke or myocardial infarction.

Page 37: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Management of hypertensive emergencies They include: hypertensive encephalopathy, acute left ventricular failure,

cerebral stroke, and aortic dissection. Management: HospitalizationRapid reduction of BP in hours not in minutes by one or more of the following

drugs: Sublingual drugs: nifedipine and captopril Parenteral drugs:Furosemide i.v.Hydralazine i.v. slowly .Diazoxide (rapid i.v. injection).Sodium nitroprusside 5 μg/kg/min i.v. infusion.Nitroglycerine i.v. infusion. Nifedipine i.v. slowly .Beta-blockers (propranolol) 1-2 mg i.v. slowly.α-methyldopa i.v.

Page 38: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Investigations:A)Basic studies for all cases:

1-Renal function tests: (urine examination-serum createnine-blood urea).

2-Plasm electrolyte level: *As a base line before diuretics therapy.

*As screen for mineralocorticoids induced hypertension.3-Blood glucose:

*As a base line before diuretics therapy. *To diagnose other conditions associated with increased blood

glucose + hypertension as pheocromocytoma…..etc4-Serum uric acid:

* As a base line before diuretics therapy.*As a risk factor for hypertension ……….(metabolic syndrome).

Page 39: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

5-Serum cholesterol:*As a base line before diuretics therapy.

*As a risk factor for hypertension ……….(metabolic syndrome).

6-Measurment of plasma rennin:7-ECG: to assess LVH and cardiac status.

Page 40: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

B) To detect secondary cause in selected cases:*Pheocromocytoma (sweating,

palpitation,headache…..)*renal arteriography in renal artery stenosis

(abdominal bruit)C) To detect occurrence of complications:

*Fundus examination.*Renal function tests.

*ECG- CXR- angiography.*EEG

Page 41: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Choice of drugs in therapy of hypertension:A) Mild or moderate hypertension:

1-Start with a single drug (monotherapy) using one of the following: (A-B-C-D). Here D refers to thiazide type diuretics.

Choice of first line therapy should be based on (type of patient and presence of concomitant diseases ).

Page 42: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

However, the preferred drug for initial therapy of mild or moderate hypertension are thiazide diuretics or beta blockers which shown to reduce cardiovascular morbidity and mortality in large clinical trials.

2 )The started drug should be started at a low dose to avoid side effects. If blood pressure remains uncontrolled, the dose is increased.

3 )If blood pressure is not controlled either change to a single drug of a different group or ADD a second drug with a different site of action e.g (thiazide +BB) or (thiazide +ACEI).

4) If hypertension is not controlled by the (two drug regimen), ADD a third drug e.g thiazide +BB+ vasodilator (ACEI or CCB or hydralazine or prazocin).

Page 43: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

B-Severe hypertension:Start by (triple therapy) using a combination of 3

drugs e.g thiazide +B B +vasodilator??????N.B :

In patients with renal impairment, thiazides are contraindicated so, loop diuretics as frusemide are recommended.

Beta blockers can be replaced with a central α2 agonist as (clonidine and α methyl dopa) if beta blockers are contraindicted.

Page 44: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

C-Hypertension resistant to triple therapy: Patients resistant to triple therapy described

above may respond to : Minoxidil + beta blocker + loop diuretics

(frusemide).ACEI + loop diuretics (frusemide) +CCB.

Page 45: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Causes of failure of treatment of hypertension:1-Non compliance with drug therapy.

2 -Inadequate drug dosage.3 -Incorrect choice of drug e.g thiazide in advanced

renal insufficiency.4-Excess salt intake.

5-Concomitant use of antagonistic drugs e.g NSAIDs ,cold remedies, oral contraceptives ….etc

6-Failue to recognize the cause of hypertension e.g pheochromocytoma or renal artery stenosis.

Page 46: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Choice of antihypertensive drugs in special situations:

Preferred drug Clinical situation

Methyl dopaα Hypertension in pregnancy

ACEI Hypertension and diabetes

CCB Hypertension and bronchial asthma

Loop diuretics (frusemide) Hypertension and renal failure

Diuretics and ACEI Hypertension and heart failure

Page 47: Therapy of hypertension By Dr. Mohamed Abd Almoneim Attia

Case 1 : A 56 year old obese male lawyer was found to have a blood pressure of

180/110mmHg during routine checkup, otherwise he was clinically free. The same BP was noted on three subsequent visits. He smoked at least 30

cigarettes a day for 20 years. How would you proceed to manage this case? 

Case 2 :A 58 year old professor complained of headache. His blood pressure was found to be 220/115 mmHg and there was no evidence of cardiac failure or renal impairment.How would you treat this patient?

 Case3 :

A 47 year old man presented with a history of attacks of chest pain provoked by exertion and relieved by rest. Exercise stress test was performed and the patient was diagnosed as (exertional angina pectoris) .How would you proceed to manage this man taking in consideration that his blood pressure

was 170/100 mmHg and that he is a heavy smoker ?