TREATMENT OF HYPERTENSION

Profs. Abdulqader Alhaider; Azza El-Medany

Department of PharmacologyCollege of Medicine

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

FACTORS IN BLOOD PRESSURE CONTROL

Hypertension

Blood pressure is determined by :

1- Blood volume

2- Cardiac output ( rate & contractility )

3- Peripheral resistance

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. Is initiated .

Indications for Drug Therapy Sustained blood pressure elevations > 140/

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 Centrally acting sympatholytic • Vasodilators (a1-antagosits; Hydralazine) • Drugs acting on renin-angiotensin

aldosterone system

B. Potassium-sparing diureticsAmiloride 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 Agents

• β- adrenoceptor blocking agents can be used in mild to moderate hypertension.

• In severe cases used in combination with other drugs.

Nadolol (non cardio selective)

Bisoprolol , Atenolol, metoprolol ( cardio selective)

Labetalol , carvidalol ( α – and β adrenergic blockers )

Beta-Adrenoceptor –Blocking Agents

• They lower blood pressure by : Decreasing cardiac output.

Decreasing renin release (very important effect and more related to the clinical response)

α1-adrenoceptor blockers

• Prazocin , Terazocin

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

CALCIUM CHANNEL BLOCKERSCALCIUM CHANNEL BLOCKERS

• Classification Dihydropyridine group (Nifedipine,

Nicardipine , Amlodipine (AmlorR) is more selective as vasodilator than a cardiac depressant. This group is used for treatment of hypertension

Verapamil is more effective as cardiac depressant , therefore it is not used

as antihypertensive agent . Diltiazem .Used mainly for angina

❏ Mechanism of Action: (Arterial) Block the influx of calcium through L-type calcium channels resulting in: 1- Peripheral vasodilatation (at arteries) 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

• Nifedipine used for Raynoids phenomena

• 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

Reflex Tachycardia

Constipation

Centrally acting sympatholytic drugs e.g. Clonidine direct

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 dopaindirect

• 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• Postural hypotension• Fluid retention & edema with chronic use• Sudden withdrawal of clonidine can lead to

rebound hypertension

VASODILATORSVASODILATORS

Compensatory Response to Vasodilators

VasodilatorsHydralazi

neMinoxidil Diazoxid

eNa

nitropruside

Site of action

Arteriodilator Arteriodilator Arteriodilator Arterio & venodilator

Mechanism of action

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

Opening of potassium channels

Release of nitric oxide ( NO)

Route of admin.

Oral Oral Rapid intravenous

Intravenous infusion

ContinueVasodilators

Hydralazine Minoxidil Diazoxide Na nitropruside

Therapeutic uses

1.Moderate -severe hypertension.CHF

1.severe hypertension

1.Hypertensive emergency( in the past )

1.Hpertensive emergency

2.Hypertensive pregnant woman

2.correction of baldness

2.Treatment of hypoglycemia due to insulinoma

ContinueVasodilators

Hydralazine Minoxidil Diazoxide Na nitropruside

Adverse effects

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

Severe hypotension

Specific adverse effects

lupus erythematosus like syndrome

Hypertrichosis.

Contraindicated in females

Inhibit insulin release from β cells of the pancreas causing hyperglycemia

Contraindicated in diabetic

1.Methemoglobinduring infusion2. Cyanide toxicity3. Thiocyanate toxicity

Give reason : β-blockers & diuretics are added to

vasodilators for treatment of hypertension?

te

Endothelium, brain &

Other Proteolytic Enzymes Chymase

Endoperoxidase

A vasoconstrictor peptide

Synthesis

Precursor is Angiotensinogen; a plasma -globulin synthesized in the liver.

Secreted by renal juxtaglomerular apparatus

AT1

AT2

Renal SN activation Renal SN activation Renal Blood flow by2 agonists & PGI2Renal Blood flow by2 agonists & PGI2Blood Pressure

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)

angiotensin-converting

enzyme

Angiotensin I(inactive)

Angiotensin II(active vasoconstrictor)

Bradykinin(active vasodilator)

Inactive metabolites

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 (use is not associated with reflex tachycardia despite causing arterioral and venous dilatation)

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+ and decrease of K+ excretion in kidney by inhibition Aldosterone secretion

Pharmacokinetics

• Captopril, Lisonopril; 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 except

Captopril• 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 . How do they work?

ADVERSE EFFECTS:

Acute renal failure, especially in patients

with bilateral renal artery stenosis

Hyperkalemia How?

(Cont’d):

Persistent cough

Angioneurotic edema (swelling in the nose , throat,tongue, larynx)

(Cont’d):

( cough & edema due to bradykinin)

severe hypotension in hypovolemic patients (due to diuretics, salt restriction or gastrointestinal fluid loss)

(Cont’d):

Taste loss

Skin rash, fever

( taste loss. is due to a sulfhydryl group in the molecule of captopril ).

Contraindications

• During the second and third trimesters of 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. How?

Drug interactions

• With potassium-sparing diuretics (e.g: Spirinolactone)

• NSAIDs impair their hypotensive effects by blocking bradykinin-mediated

vasodilatation.

BLOCKERS OF AT1 RECEPTORlosartan, valosartan, 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

Losartan, valsartan , irbesartan

Adverse effects• As ACEI except cough,wheezing, and

angioedema.

• Same contraindications as ACEI.

Drug Combination for Hypertension

• Hydrochlorothiazide (12.5 mg+ Valsartan • (60 or 80 mg) (Co-DiovanR)• Hydrochlorothiazide (12.5 mg + Losartan (50 or 100 mg)• Hydrochlorothiazide (12.5 mg + Lisinopril

(10 or 20 mg)

Drugs for treatment of hypertensive crisis

• Labetalol• Hydralazine (in pregnancy)

• Sodium nitroprusside (2nd line)General characters of good drug for Crisis:• Fast & short acting• Given by IV

THANK YOU