Renin-Angiotensin System Drugs Igor Spigelman, Ph.D. Division of Oral Biology & Medicine, UCLA...
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Transcript of Renin-Angiotensin System Drugs Igor Spigelman, Ph.D. Division of Oral Biology & Medicine, UCLA...
Renin-Angiotensin System Drugs
Igor Spigelman, Ph.D.
Division of Oral Biology & Medicine, UCLA School of Dentistry, CA
Rm. 63-078 CHS
Email: [email protected]
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
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)