Targets for Antihypertensive Drugs Flashcards
What does renin do?
cleaves angiotensinogen to angiotensin I
What does kallikrein do?
cleaves kininogen to bradykinin
What does angiotensin-converting enzyme do?
converts angiotensin I to angiotensin II and inactives bradykinin
What does bradykinin do in the body?
vasodilation, decreased peripheral vascular resistance, decreased blood pressure
What does angiotensin II do in the body?
vasoconstriction -> increased peripheral vascular resistance
aldosterone secretion -> increased sodium and water retension
INCREASES BLOOD PRESSURE
What does aminopeptidase do?
converts angiotensin II to angiotensin III
What does angiotensinases do?
breaks down angiotensin III
What does prorenin do besides act as a precursor for renin?
prorenin has a receptor itself and its activity regulates the renin-angiotensin system and plays a role in other stuff
Primary biologically active molecule in the renin-angiotensin system?
angiotensin II
Name the three pathways that control renin release.
- NaCl reabsorption at macula dense
- blood pressure in pre-glomerular vessels
- activation of beta1 adrenergic receptors on JGCs
Angiotensin II Type 1 (AT1) receptors
G-protein coupled; Gi and Gq
also couples to phospholipase A2
Where are AT1 receptors located?
blood vessels, brain, adrenals, kidney, and heart
Activation of AT1 receptors works to
increase BP through vasoconstriction and Na+/water reabsorption
Name three things that angiotensin II alters
- altered peripheral resistance
- altered renal function
- altered cardiovascular structure
How does angiotensin II alter peripheral resistance?
- direct vasoconstriction
- enhancement of peripheral noradrenergic neurotransmission (increased NE release, decreased NE reuptake, increased vascular response)
- increased sympathetic discharge
- release of catecholamines from adrenal medulla
Result of altered peripheral resistance from angiotensin II
rapid pressor reponse (increased bp)
How does angiotensin II alter renal function?
- direct effect to increase Na+ reabsorption in proximal tubule
- release of aldosterone from adrenal cortex
- altered renal hemodynamics (direct renal vasoconstrictoin, enhanced noradrenergic neurotransmission in kidney, increased renal sympathetic tone)
Result of altered renal function from angiotensin II?
slow pressor response (Na+ and water retention)
How does angiotensin II alter cardiovascular structure?
I. non-hemodynamically mediated effects (increased expression of proto-oncogenes, increased GFs, increased synthesis of extracellular matrix proteins)
II. Hemodynamically mediated effects (increased afterload, increased wall tension)
Result of altered cardiovascular structure from angiotensin II?
vascular and cardiac hypertrophy and remodeling
Three classes of drugs that inhibit the renin-angiotensin system
- direct renin inhibitors
- ACE inhibitors
- Angiotensin receptor blockers
Sulfhydryl-containing ACE inhibitor
captopril (capoten)
Dicarboxyl-containing ACE inhibitor
enalopril (vasotec)
Phosphorous-containing ACE inhibitor
fosinopril sodium (monopril)
What class of drugs would interfere with bradykinin-mediated vasodilation?
NSAIDs
What is the effect of ACE inhibitors on bradykinin?
bradykinin is not inactivated, so more is available to promote vasodilation and decrease blood pressure
What is the effect of ACE inhibitors on angiotension II?
decreased angiotensin II, so blood pressure is decreased
Side effects of sulfhydryl-containing ACE inhibitors (captopril)
altered taste (metallic) and rash
What is significant about Moexipril?
only ACE inhibitor cleared through hepatic metabolism (dose doesn’t have to be adjusted in patients with compromised renal function)
Dicarboxyl-containing ACE inhibitor (Enalopril) requires
requires hydrolysis of ethyl ester to form active diacid form, enalaprilat (soluble form); enalopril is a pro-drug
Parenteral dosage forms of ACE inhibitors end in which suffix?
-PRILAT
Lysine-derivative of enalaprilat
Lisinopril (dicarboxyl-containing ACE inhibitor)
Clinical uses of ACE inhibitors
hypertension, left ventricular systolic dysfunction, myocardial infarction, diabetic nephropathy (prevention)
Adverse effects of ACE inhibitors
hypotension, dry cough, hyperkalemia, acute renal failure, skin rash (captopril), angioedema (contraindication)
Drug-drug interactions of ACE inhibitors
antacids (reduce bioavailability), NSAIDs may reduce effectiveness, K+ supplements, may increase plasma levels of digoxin and lithium
Contraindications of ACE inhibitors
pregnancy, high doses in patients with renal insufficiency may lead to neutrpenia
Angiotensin II type 1 receptor antgaonists
“the sartans”
losartan potassium; valsartan; irbesartan; candesartan cilexetil; temisartan; eprosartan mesylate
Actions of angiotensin II type 1 receptor (AT1) antagonists
selective blocks effects of angiotensin II: pressor effects, stimulation of NE system, secretion of aldosterone, effects on renal vasculature, growth-promoting effects on cardiac and vascular tissue
uricosuric effect
What system does AT1 antagonists NOT effect
no effect on bradykinin system
What do angiotensin II receptor antagonists provide more complete inhibition of the action of angiotensin II as compared to ACE inhibitors?
Angiotensin III also works on these receptors
Clinical uses of AT1 receptor antagonists
hypertension, CHF, diabetic nephropathy, stroke prophylaxis
Adverse effects of AT1 receptor antagonists
hypotension, hyperkalemia, teratogenic potential
Renin inhibitor
Aliskiren (Tekturna)
How does Aliskirin work?
direct renin inhibition; dipeptide like mimetic
Aliskiren used to treat
used alone or in combination to treat hypertension
What decreases the absorption of Aliskirin
high-fat meals
Side effects of Aliskirin
diarrhea
Contraindications for Aliskirin
contraindicated in pregnancy and nursing mothers
