Vasoactive peptides and inhibitors, Antihypertensive Vasodilator Drugs 1 and 2 Flashcards
Components of blood pressure
CO (SV,HR) * SVR (PVR,RVR)
What is hypertension?
high blood pressure mostly due to sympathetic activity leading to elevated vascular resistance
Site of action: carbonic anhydrase inhibitors
proximal convoluted tubule
Site of action: thiazides
distal convoluted tubule
MOA: diuretics
na loss –> fluid loss –> reduce blood volume –> reduce CO –> reduce bp
How does the body compensate for long-term use of diuretics?
reduce plasma volume –> increase renin/aldosterone –> increase K+ loss/Na+ retention –> distal fluid reabsorption
- net effect = lower ECF volume –> lower BP even in the face of compensation
- likely secondary MOA by reduce PVR via NO
In which population do we have to be careful when prescribing thiazide diuretics and why?
elderly –> long duration of action = dehydration in older people
Who is most responsive to thiazide diuretics?
african americans and elderly –> response depends on vigor of adaptation process, response reduced in chronic renal insufficiency
Thiazide risks
sulfa allergy, hypokalemia, promotes insulin resistance by increasing plasma glucose, increase Tg/LDL cholesterol
Which tissues are most affected by calcium channel antagonists, why?
cardiac and smooth muscle –> rely on influx of extracellular calcium for depolarization
What kind of channels are blocked by most calcium channel antagonists?
L-type
2 classes of CCAs?
non dhpr, dhpr
When do nondhpr CCAs bind the L channel?
when they are open –> if frequency of stimulation is increased, (e.g. rapid arrhythmia), increased blockade
*nondphr is better in myocytes than in VSMC
When do dhpr CCAs bind the L channel?
resting state –> better binding in VSMCs
Indication for verapamil
superventricular arrhythmia and hypertension, non dhpr
Indication for diltiazem
superventricular arrhythmia + some hypertension, non dphr
Indication for nifedipine
hypertension, dphr
Danger of using DHPR
increase in HR, SVR, and RAAS as a reflex to peripheral vasodilation –> increased work of heart in those being treated for …their heart
4 stimulators of renin
- hypovolemia
- hyponatremia
- hypotension
- adrenergic activation
Rate limiting step in RAAS
renin conversion of angiotensinogen to angiotensin 1
What is the negative feedback for the action of renin?
systemic levels of angiotensin ii and amount of angiotensin ii bound to its receptors
The vasoconstrictive properties of Angiotensin II is mediated by what receptor?
AT1
Where are AT1 and AT2 receptors found?
AT1: vsm, kidney, adrenal, cortex, pituitary
AT2: uterus, fetus but can be INDUCED
Effect of binding of angiotensin ii to AT1
vasoconstriction –> aldosterone release, cell proliferation, hypertrophy, matrix deposition
Effect of binding of angiotensin ii to AT2
vasodilation –> bradykinin, NO, cGMP, antiproliferation, apoptosis
Response to angiotensin ii in brain
- increase in sympathetic discharge
- release of ADH/ACTH (endocrine response)
- thirst and sodium appetite
Response to angiotensin ii in adrenal medulla
release of catecholamines
Response to angiotensin ii in peripheral vasculature
increases release/decreases uptake of NE, enhances sensitivity of NE –> vasoconstriction
Response to angiotensin ii in adrenal cortex
stimulates synthesis and release of aldosterone from ZG –> augmented by hyponatremia and hyperkalemia
Response to angiotensin ii in kidney
antidiuresis/antinatriuresis, reduced gfr, inhibit renin
CVD effects of angiotensin ii
- hypertension
- cell proliferation/apoptosis, hypertrophy
- proinflammatory: impairs endothelial function (e.g. leads to oxidation of LDLR to oxLDLR), induces oxidation
As angiotensin ii levels rise, ____ is activated leading to the proliferation of inflammatory cytokines like ___, ____, and ___.
nfkb –> vcam1, mcp1, il6 (CRP)
Limitations of ACE inhibitors
non-specificity of enzyme, alternate pathways for production, poor side effect profile
What 3 enzymes catalyze the production of AngII directly from angiotensinogen?
tpa, cathepsin G, tonin
What 3 enzymes catalyze the production of AngII from AngI w/o ACE?
CAGE, cathepsin G chymase
What is ACE escape?
after inhibiting ACE, angiotensin II levels can recover and exceed beginning b/c of secondary pathways like cathepsin G, chymase, etc.
Despite ACE escape, ACE inhibitors reduce blood pressure. Why?
ACE is non specific –> also breaks down bradykinin thereby preventing vasodilation –> ACE inhibitors block this process and promote vasodilation
Most common side effects of ACE-I
cough, angioedema, renal dysfunction, hypotension
What do ARBs do to the negative feedback loop to renin?
receptor binding is 1 of 2 factors (the other being serum angII) that reduce renin production –> ARBs prevent this so reduce negative feedback (more renin)–> more ang ii to bind to at2 receptors (vasodilatory effect)
What do ARBs do to the negative feedback loop to renin?
receptor blockade is 1 of 2 factors (the other being serum angII) that reduce renin production
What do ARBs do to the negative feedback loop to renin?
receptor binding is 1 of 2 factors (the other being serum angII) that reduce renin production –> ARBs prevent this so reduce negative feedback (more renin)–> more ang ii to bind to at2 receptors (vasodilatory effect)
What is the impact of DRI on outcomes?
no difference between inhibiting renin and using traditional therapies (ACEI, ARB, diuretics)
What happens to PRA, Ang I level, Ang II level with: diuretics
up up up
What happens to PRA, Ang I level, Ang II level with: renin inhibitor
down down down
What happens to PRA, Ang I level, Ang II level with: ARB
up up up
What happens to PRA, Ang I level, Ang II level with: renin inhibitor
down down down
