Renin-Angiotensin System Drugs

Igor Spigelman, Ph.D.

Division of Oral Biology & Medicine, UCLA School of Dentistry, CA

Rm. 63-078 CHS

Email: igor@ucla.edu

RENIN-ANGIOTENSIN SYSTEM

Control of renin secretion:

• Mechanical

• Ionic

• NE release

- plays a major role in the regulation of hemodynamics and water and electrolyte balance via its circulating hormone, angiotensin II.

Renin: rate-limiting enzyme in angiotensin II production

Blood PressureRises

Vasoconstriction

- +

A schematic portrayal of the homeostatic roles of the renin-angiotensin system

Blood VolumeRises

ReninRelease

Na+ Retention

AldosteroneSecretion

Na+ Depletion

Blood VolumeFalls

Blood PressureFalls

AngiotensinFormation

ANGIOTENSIN II

AlteredPeripheralResistance

AlteredRenal

Function

AlteredCardiovascular

Structure

Rapid Pressor Response Slow Pressor ResponseVascular + Cardiac

Hypertrophy + Remodeling

I. Direct vasoconstriction

II. Enhancement of peripheral noradrenergic neurotransmission

III. Increased sympathetic discharge (CNS)

IV. Catecholamine release from adrenal medulla

I. Increased Na reabsorption by proximal tubule

II. Increased aldosterone release

III. Altered renal hemodynamics (vasoconstriction)

+ I. Stimulation of cell growth

II. Hemodynamic changes

A. Increased cardiac afterload + preload

B. Increased vascular wall tension

ACE InhibitorsActive molecules:Captopril, Lisinopril, Enalaprilat

Prodrugs:Enalapril, Benazepril, Fosinopril, Quinapril, Ramipril, Moexipril, Spirapril

Beneficial effects in:

Hypertension

CHF

Adverse effects of ACE Inhibitors• Hypotension

• Renal insufficiency

• Cough

• Hyperkalemia

• Hyperreninemia

• Ageusia

• Skin rash

• Proteinuria

• Neutropenia

AT-Receptor Antagonists

Losartan,Valsartan, Candesartan, *sartan

Non-peptide competitive inhibitors of AT1 receptors. Block ability of angiotensins II and III to stimulate pressor and cell proliferative effects.

Antihypertensive effects Cell growth effects Lack of “bradykinin” effects

Renin Inhibitors- angiotensinogen analogs show promise

- elevation of systolic/diastolic pressure above 140/90 mm Hg- most common cardiovascular disease in USA

Essential

HYPERTENSION

Secondary

Unknown etiology80-90% of all casesTreatment mainly symptomatic

Known etiologyTreat to eliminatecause of the disease

Mortality Is Related to Blood Pressure

Clinical disorders resulting fromhypertension and atherosclerosis

• Congestive heart failure

• Cerebral hemorrhage

• Renal failure

• Retinopathy

• Dissecting aneurysm

• Hypertensive crisis

• Coronary artery disease

• Angina pectoris

• Myocardial infarction

• 2° renovascular hypertension

• Peripheral vascular insufficiency

• Cerebral thrombosis - stroke

Hypertension Atherosclerosis

AgeSexRaceHyperlipoproteinemiaDiabetes mellitusCigarette smoking

ObesitySalt intakePrevious cardiovascular diseaseFamily history of cardiovascular disease

Risk factors for cardiovascular complications in hypertensive subjects

cardiac output (ß-blockers, Ca2+

channel blockers)

plasma volume (diuretics)

peripheral vascular resistance (vasodilators)

MAP = CO X TPR

PharmacotherapyNon-pharmacological

TREATMENT OF HYPERTENSION

• Restriction of salt intake

• Reduction of body weight

"Individualized Care"

• Risk factors considered• Non-pharmacological therapy tried first• Monotherapy is instituted• Considerations for choice of initial

monotherapy: Renin status Coexisting cardiovascular

conditions Other conditions

• ACE inhibitors• ATII antagonists• Diuretics -adrenoceptor blockers

• 1-adrenoceptor blockers

• Ca2+ channel blockers

MONOTHERAPY

• Centrally acting antihypertensives

• Guanethidine• Minoxidil• Hydralazine

Drugs used only in combination

PHARMACOTHERAPY OF HYPERTENSION

Sites of action of drugs that relax vascular smooth muscle

Angiotensin II receptorantagonists

LosartanValsartan

Ca2+-channel blockers

DihydropyridinesVerapamilDiltiazem

K+-channel activatorsMinoxidilDiazoxide

Activators of theNO/guanylate cyclase pathway

HydralazineNitroglycerinNitroprusside

-Adrenoceptorantagonists

PrazosinTerazosin

K+

Ca2+

NO

HYPERTENSIVE EMERGENCIES

Sodium nitroprusside

Glyceryl trinitrate

Trimethaphan

Hydralazine

Parenteraladministration

e.g. cerebral hemorrhage, myocardial infarction

Implications for Dentistry

• Care in use of vasoconstrictors (e.g. supersensitivity to catecholamines with guanethidine)

• Orthostatic hypotention (common to all antihypertensive drugs)

• Judicious use of CNS depressants (esp. with centrally-acting antihypertensive drugs)

• Salivary inhibition (xerostomia common with centrally-acting antihypertensive drugs)

• NSAIDs (decrease action of captopril, spironolactone, furosemide)

• Gingival hyperplasia (with long-term use of Ca2+channel blockers)