TREATMENT OF HYPERTENSION

Prof. Azza El-Medany

Department of Pharmacology

OBJECTIVES

• At the end of lectures , the students should :• Identify factors that control blood pressure• Identify the pharmacologic classes of drugs

used in treatment of hypertension• Know examples of each class.

OBJECTIVES ( continue)

• Describe the mechanism of action , therapeutic uses & common adverse effects of each class of drugs including :

• Adrenoceptor blocking drugs ( β & α blocking drugs )

• Diuretics• Calcium channel blocking drugs• Vasodilators

OBJECTIVES ( cont.)

• Converting enzyme inhibitors • Angiotensin receptor blockers.• Describe the advantages of ARBs over ACEI

Hypertension

Blood pressure is determined by :

1- Blood volume

2- Cardiac output ( rate & contractility )

3- Peripheral resistance

FACTORS IN BLOOD PRESSURE CONTROL

i

Hypertension

• Is a major risk factor for cerebrovascular

disease, heart failure, renal insufficiency

and myocardial infarction.It is often asymptomatic until organ damages

reaches a critical point.

Antihypertensive therapy

• Initially consists of lifestyle changes , such as weight reduction , smoking cessation,

reduction of salt, saturated fat, , excessive alcohol intake , and increased exercise

before drug therapy.

Indications for Drug Therapy Sustained blood pressure elevations > 150/ 90

mmHg. when minimally elevated blood pressure is

associated with other cardiovascular risk factors (smoking, diabetes, obesity, hyperlipidemia, genetic predisposition ).

When end organs are affected by hypertension (heart, kidney , brain ).

Drug Management of Hypertension

Diuretics Cardio inhibitory drugs Beta- blockers Calcium –channel blockers α adrenoceptor blockersCentrally acting sympatholytic Vasodilators Drugs acting on renin-angiotensin

aldosterone system

Diuretics

-A: thiazides ( hydrochlorothiazide) B: Loop diuretics ( furosemide ) ► cause sodium and water loss decrease volume of blood decrease cardiac output lower blood pressure. ►Thiazide may be adequate in mild hypertension Loop agents used in moderate & severe hypertension

C.Potassium-sparing diuretics

Amiloride as well as spironolactone

reduce potassium loss in the urine.

Spironolactone has the additional benefit of diminishing

the cardiac remodeling that occurs in heart failure.

Cardio inhibitory Drugs

β -Adrenoceptor –Blocking DRUGS

• Are used as monotherapy in mild to moderate hypertension.

• In severe cases used in combination with other drugs.

e.g.

Nadolol , Propranolol ( non cardio selective)

Bisoprolol , Atenolol, metoprolol ( cardio selective)

Labetalol , carvidalol ( α – and β adrenergic blockers )

Beta Adrenoceptor –Blocking DRUGS

Non cardioselective (β1 & β2 ) drugs as propranolol

( contraindicated in patients with asthmatic patients).

Antihypertensive effects of Beta –adrenergic receptor blocking drugs

• Decreases sympathetic tone → ↓ HR & CO Myocardial contractility

• Decrease renin release

CALCIUM CHANNEL BLOCKERSCALCIUM CHANNEL BLOCKERS

• Classification Dihydropyridine group (nifedipine, nicardipine , amlodipine )

more selective as vasodilator than a cardiac depressant. This group is used for treatment of hypertension

• Classification ( continue) Verapamil is more effective as

cardiac depressant , therefore it is not used as antihypertensive agent, used as antiarrhythmic .

Diltiazem .Used mainly for treatment of angina

Mechanism of action ❏ Block the influx of calcium through L-type calcium channels resulting in: 1- Peripheral vasodilatation 2- Decrease cardiac contractility & heart rate

Both effects lower blood pressure

Pharmacokinetics:❏ given orally and intravenous injection

❏ well absorbed from G.I.T

❏ verapamil and nifedipine are highly bound to plasma protiens ( more than 90%) while diltiazem is less ( 70-80%)

(Cont’d):

❏ onset of action --- within 1-3 min --- after i.v. 30 min – 2 h --- after oral dose

❏ verapamil & diltiazem have active metabolites, nifedipine does not

❏ sustained-release preparations can permit once-daily dosing

Clinical uses

• Treatment of chronic hypertension with oral preparation

• Nicardipine can be given by I.V. route & used in hypertensive emergency

ADVERSE EFFECTSVerapamil Diltiazem Nifedipine

Headache , Flushing , Hypotension

Headache, Flushing, Hypotension

Headache , Flushing, Hypotension

Peripheral edema (ankle edema)

Peripheral edema (ankle edema)

Peripheral edema (ankle edema)

Cardiac depression, A-V block , bradycardia

Cardiac depression , A-V block , bradycardia

Tachycardia

Constipation

α-adrenoceptor blockers

• Prazocin , terazocin Selectively block postsynaptic α1 adrenergic

receptors. They dilate arterioles → lowering BP

• Added to β- blockers for treatment of hypertension of pheochromocytoma

Centrally acting sympatholytic drugs

e.g. Clonidine

α2-agonist Reduce sympathetic outflow to the

heart thereby decreasing cardiac output ( by decreasing heart rate

& contractility ).Reduced sympathetic output to

the vasculature, decreases sympathetic vascular tone , which causes vasodilation & reduced systemic vascular resistance, which decreases arterial pressure.

α methyl dopa

• α 2 agonist is converted to methyl norepinephrine centrally to diminish the adrenergic outflow from the C.N.S. This lead to reduced total peripheral resistance, and a decreased blood pressure.

• Safely used in hypertensive pregnant women

Side effects of centrally acting sympatholyics

• Depression

• Dry mouth & nasal mucosa

• Bradycardia

• Impotence

Side effects ( continue)

• Fluid retention & edema with chronic use

• Abrupt cessation of clonidine may cause a serious rebound hypertension

• Hemolytic anemia ( methyldopa is the only antihypertensive drug associated with hemolytic anemia usually preceded by a positive Coombs, test.

VASODILATORSVASODILATORS

Compensatory Response to Vasodilators

VasodilatorsHdralazin

eMinoxidil Na

nitroprusside

Site of action

Arteriodilator Arteriodilator Arterio & venodilator

Mechanism of action

Direct Opening of potassium channels in smooth muscle membranes by minoxidil sulfate ( active metabolite )

Release of nitric oxide ( NO)

Route of admin.

Oral Oral Intravenous infusion

ContinueVasodilators

Hdralazine Minoxidil Na nitropruside

Therapeutic uses

1.Moderate -severe hypertension.CHF

1.Moderate –severe hypertension

1.Hpertensive emergency

2.Hypertensive pregnant woman

2.correction of baldness

ContinueVasodilators

Hdralazine Minoxidil Na nitroprusside

Adverse effects Hypotension, reflex tachycardia, palpitation, angina, salt and water retention ( edema)

Hypotension, reflex tachycardia, palpitation, angina, salt and water retention ( edema)

Severe hypotension

Specific adverse effects

lupus erythematosus like syndrome

Hypertrichosis.

Contraindicated in females

1.Methemoglobinduring infusion2. Cyanide toxicity3. Thiocyanate toxicity

Give reason : β-blockers & diuretics are added to

vasodilators for treatment of hypertension?

te

angiotensin-converting

enzyme

Angiotensin I(inactive)

Angiotensin II(active vasoconstrictor)

Bradykinin(active vasodilator)

Inactive metabolites

ACE inhibitors

Mechanism of action of Angiotensin-converting enzyme inhibitors (ACEI)

Mechanism of action:

Converting enzyme inhibitors lower blood pressure by reducing angiotensin II, and also by increasing

vasodilator peptides such as bradykinin.

Reduction of sympathetic activity Inhibition of aldosterone secretion

Reduce the arteriolar and left ventricular remodelling that are

believed to be important in the pathogenesis of human essential

hypertension and post-infarction state

Dilatation of arteriol reduction of peripheral vascular resistance ( ↓afterload )

Increase of Na+ & water excretion in kidney( ↓preload)

Decrease of K+ excretion in kidney

Pharmacokinetics

• Captopril, enalapril and ramipril .• All are rapidly absorbed from GIT after oral

administration.• Food reduce their bioavailability.• Enalapril , ramipril are prodrugs, converted to the

active metabolite in the liver • Have a long half-life & given once daily• Enalaprilat is the active metabolite of enalapril given by i.v.

route in hypertensive emergency.

Phrmacokinetics

• Captopril is not a prodrug

• Has a short half-life & given twice /day

• All ACEI are distributed to all tissues except CNS.

Clinical uses Treatment of hypertension

Treatment of heart failure

Diabetic nephropathy .

ADVERSE EFFECTS:

Acute renal failure, especially in patients

with bilateral renal artery stenosis

Hyperkalemia

Persistent cough

Angioneurotic edema

(Cont’d):

( cough & angioneurotic edema due to increase in bradykinins)

severe hypotension in hypovolemic patients

(due to diuretics, salt restriction or gastrointestinal fluid loss)

(Cont’d):

Taste loss ( due to SH group in captopril molecule)

Skin rash, fever

Contraindications

• Is absolutely contraindicated pregnancy due to the risk of : fetal hypotension ,anuria ,renal failure &

malformations .• Bilateral renal artery stenosis or stenosis of a renal

artery with solitary kidney causing acute renal failure.

Drug interactions

• With potassium-sparing diuretics • NSAIDs impair their hypotensive effects by blocking bradykinin-mediated

vasodilatation.

N.B.Less effective in African American Patients as

monotherapy

BLOCKERS OF AT1 RECEPTORlosartan, valsartan, irbesartan

- competitively inhibit angiotensin II at its AT1 receptor site

most of the effects of angiotensin II - including vasoconstriction and aldosterone release - are mediated by the AT1 receptorthey influence RAS more effective because of selective blockade (angiotensin II synthesis in tissue is not completely dependent only on renin release, but could be promote by serin- protease -

angiotensinogen

angiotensin I

angiotensin II

renin

ACE

nonrenin proteasescathepsin

t-PAchymaseCAGE

Continue

They have no effect on bradykinin system

causing neither: cough, wheezing nor

angioedema

Adverse effects• As ACEI except cough ,wheezing , and

angioedema.

• Same contraindications as ACEI.

Drugs used for management of hypertensive emergencies

BP > 180/120 mmHg associated with end-organ damage•Sodium nitroprusside•Hydralazine •Nicardipine•Enalaprilat•Labetalol

Precaution in management of hypertensive emergencies

Avoid using short-acting nifedipine because of the risk of rapid , unpredictable hypotension & the possibility of precipitating ischemic events

Drugs used for management of hypertension in pregnancy

• Methyldopa ( the preferred first line )• Labetalol• Hydralazine• Diuretics

THANK YOU