Vasoactive Peptides & Inhibitors Flashcards
(51 cards)
1
Q
- where is angiotensinogen synthesized?
- what does it become and due to what enzymes?
- how is its synthesis regulated?
A
- synthesized in the liver
- converted by renin to angiotensin I
- renin released by juxtaglomerlar cells on afferent arteriole in response to
- NE/EPI release during hypovolemic state (low BP, low NaCl)
- renin released by juxtaglomerlar cells on afferent arteriole in response to
- angiotensin I converted to angiotensin II
- angiotensin II inhibits renin release
- antiogensin II –> III –> IV
2
Q
antiotensin II receptors
- where are they found?
- what does stimulation by angiotensin cause?
A
- AT1 receptors
- found in the vascular smooth muscle
- stimulates PLC in membrane
- PLC stimulation results in IP3 release (from PIP2)
- IP3 release causes Ca++ release –> smooth muscle contraction
- –> vasoconstriction
- AT2 receptors
- found in fetal tissues
- angiotensin II binding maintains healthy tissues
- possibly found on endothelium and involved in NO mediated vasodilation
3
Q
effects of AT1- angtiotensin II binding
A
- SNS outflow: release of catecholamines from nerve terminals
- cardiac:
- hypertrophy of cardiac and vascular muscle
- vasoconstriction
- CNS:
- perception of thirst to promote fluid intake
- ADH release
- ADH released from hypothalamus
- ADH increases water reabsorption
- ADH released from hypothalamus
- kidney: aldosterone release
- rentention of Na+ and fluid
4
Q
pathological effects of angiotensin II
A
- hypertension (by vasoconstriction/increasing blood volume)
- heart failure (hypertension increases afterload against which the heart may word)
- cardiac remodeling after MI (causes hypertrophy)
- chronic renal diseases (efferent arterioles constriction increases glomerular hydrostatic pressure, injuring glomerulus)
5
Q
list the classes of drugs that inhibit angiotensin II’s pathological effects
A
= inhibition of RAAS system
- renin inhibitors: inhibit conversion of antiotensinogen to angiotensin I
- ACE inhibitors: inhibit conversion of angiotensin I to angiotensin II
- AT receptor blockers
6
Q
what three factors can increases renin release?
A
- drop in tubular NaCl
- low blood pressure
- stimulation of B1 receptors
7
Q
aliskiren
- what kind of RAAS inhibitor
- MOA
A
- renin inhibitor: inhibits renin function
- MOA binds to renin and inhibits its function
- this inhibits the conversion of angiotensin to angiotensin I
- this subsequently decreases production of angiotensin II
- decrease in angiotensin II releases the negative feedback inhibition that it typically has over renin
- ends up causing renin secretion to actally i_ncrease_
- decrease in angiotensin II releases the negative feedback inhibition that it typically has over renin
8
Q
ACE inhibitors MOA
A
ACE inhibitors
- inhibit conversion of angiotensin I to angiotensin II
- inhibit breakdown of bradykinin to inactive form, thus increasing concentration of bradykinin (a vasodilator)
* this contributes to anti-hypertensive effects mediated by antiogensin II decrease
9
Q
AEs seen in ACE inhibitors but not ARBs
A
can cause a persistent dry cough - this is due increase in bradykinin
10
Q
AT1 antagonists
- MOA
- indication
A
- MOA: bind AT1 receptors (found on smooth muscle vasculature) and inhibit binding of angiotensin
- indications: used in hypertensive patients who cannot tolerate the persistent dry cough caused by ACE inhibitors
- this is because they do NOT cause in increase in bradykinin like ACE inhibitors
11
Q
effects of RAAS inhibition on cardiovascular system:
A
- decrease sympathetic nervous system
- decrease cardiovascular remodeling by
- inhibiting cardiovascular hypertrophy, and
- lowering work on the heart (pre-load and afterload), by
- inhibiting vasoconstriction
- reduceing blood volume
- by inhibiting ADH and aldosterone
12
Q
renal effects of RAAS inhibition
A
-
reduce proteinurea
- proteinurea = presence of proteins in the urine due to damage of the glomerular capillaries
- constant increased glomerular pressure promotes filtration of otherwise not filtered proteins –> protein in the urine –> proteinurea
- RAAS inhibition:
- leads to vasodilation of the efferent arteriole, thus preventing high glomerular pressure
- proteinurea = presence of proteins in the urine due to damage of the glomerular capillaries
-
reduce risks of type 2 diabetes
- increase insulin sensitivity?
13
Q
list the increases in RAAS products that will be seen as a result of renin inhibition, ACE inhibitors, and AT1 blocker
A
- Renin enzyme inhibitor: increase renin release
- ACE inhibitors: increase renin, Ang I
- AT1 blockers: increase renin, Ang I and II
14
Q
what are the ACE inhibitors?
A
“prils”
captopril, lisonopril
15
Q
what are the AT1 Receptor blockers (ARBs)?
A
“sartans”
losartan, valsartan
16
Q
what renin enzyme inhibitor did we discuss?
A
aliskiren
17
Q
uses of ACE inhibitors
A
- hypertension
- heart failure
- acute MI
- chronic renal disease: slows the rate of decline in renal function
- reducing intra-glomular pressure
- increasing selectivity of glomerular filtering membrane
18
Q
diabetic kidney disease
- discuss the pathology
- why are ACE inhibitors an effetive treatment?
A
- diabetic kidney disease is characterized by mesangial expansion and glomerular basement thickening
- this causes contraction of the arterioles
- leads to a decrease in surface area of the basement membrane
- decreased surface area –> decreased GRF
- ACE inhibitors:
- dilate renal arterioles
- decrease glomelular capillary pressure
- decreased glomerular injury –> surface area restored –> restored GFR
- decrease glomelular capillary pressure
- increase selecitivty of filtering membrane
- such that growth factors are not leaking out into filtrate, damaging mesangium
- dilate renal arterioles
19
Q
clinical uses of AT1 receptor antagonists (ARBs)
A
same as ACE inhibitors- hypertension, heart failure, chronic kidney disease, acute mi
indicated especially in someone intolerant to persistent dry cough
20
Q
use of aliskiren
A
(renin enzyme inhibitor)
use = hypertension (not the first line though)
21
Q
AEs of RAS inhibitors
A
ACE inhibitors, ARBs and renin inhibitor:
- hypotension
- headache, dizziness
- GI disturbances
-
renal function impairment
- ang II inhibition will vasodilate efferent arteriole, lowering glomular hydrastatic pressure. though this protects the glomerulus, it does decrease GFR. somebody with impaired renal function already has a low GFR, and adding an ACE inhibitor/ARB could be dangerous
-
hyperkalmia
- Ang II production stimulates aldsosterone secretion. aldstonerone stimulates Na/K exchanger that reabsorbs Na+ in exchanger for K+ secretion. inhibition of Ang II and thus aldosterone will slow K+ secretion thus causig K+ retention
ACE inhibitors specifically: cause the following AEs as a result of increasing bradykinin levels
- persistent dry cough
- angioedema
22
Q
drug drug interactions of RAS inhibitors:
A
- NSAIDS longer than five days:
- they counteract the anti-hypertenive effects of RAS inhibitors
- trimethoprim other K+ sparing diuretics
- these drugs increase serum potassium
- hyperkalemic effects of RAS inhibitors coud be dangers
- litium - can cause lithium toxicity
23
Q
mechanism by which co-administration of trimethoprim and RAS inhibitors can cause hyperkalmia
A
- in the principle cells of collecting tubules
- Na+ reabsorption leaves a negative intraluminal charge
- this draws K+ into the the filtrate
- trimethoprim behaves like a K+ sparing diuretic. in combination with RAS inhibitors, which inhibit aldosterone thus inhibiting K+ secretion, this can lead to hyperkalemia
24
Q
contraindications of RAS inhibitors
A
- pregnancy
- pts with bilateral renal artery stenosis:
- these patients are hypoperfused
- RAS inhibitors will lower GRF further impairing renal function
25
what is the kallikrein-kinin system?
* system that generates bradykinin from kiniogen
* bradykinin binds to B2 receptors to cause **vasodilation** other possible consequent pathological effects:
* increased vascular permeability
* angioedema
* inflammation
26
dicuss the classes of drugs that effect the kallikriein kinin system, and their general systemic ffects
* drugs that **decrease** the vasodilatory effects of bradykinin
* kallikrin inhibitors
* inhibit conversion of kinogen to bradykinin
* B2 receptor antagonists
* drugs that **promote** effects of bradykinin
* ACE inhibitors:
* inhibit degradation of bradykinin
27
icatibant
- what kind of drug
- MOA
- uses
* MOA: B2 receptor antagonists
* inhibits effects of kallikrine-kinin system
* indication:
* _hereditary_ and _drug induced_ **angioedema**
28
what are the kellikrein inhibitors?
what are their uses?
* drugs:
* aproptinin
* ecallantide
* lanadelumab
* use: **hereditary angioedema**
29
natriuretic peptides
* where are they synthesized?
* in what circumstances are they released?
* what is their role ?
* natruiretic peptides = ANP, BNP
* they are synthesized in the heart
* released in response to high:
* cardiac disention
* sympathetic stimulation
* angiotensin
* endothelin (vasoconstrictor)
* NPs lower BP in a host host of ways:
* **vasodilation --\>** lowers BP
* **inhibition of renin** production by the kidney: this decreases Ang II --\> thus aldosterone, inhibiting Na+ reabsorption leading to
* **nautiuresis diuresis** **(salt excretion**)
* water follows
* blood pressure drops
* --\> lower BP
30
cardiovascular effects of natriuretic peptides
* direct vasodilation
* supression of RAS, inhibiting secretion of vasoconstrictors (angiotensin)
together, this reduces afterload/preload and work on the heart
31
renal effects of ANPs/BNPs
* vasodilation --\> increased blood flow --\> increase GFR
* reduce renin release
* decrease AngII aldosterone
* --\> increased Na+ excretion (natruiresis)
32
what is nesiritide?
BNP agonist, mimicks effects of BNP
33
nesitiride
- MOA
- uses
* MOA: is recombinant BNP that behaves like BNP and reduces cariac workload by lowering blood pressure via vasodilation, diuresis, natriuesis
* clinical uses
* acute decompensated heart failure
34
what is sacubitril?
an ANP/BNP metabolism inhibitor
35
sacubitril MOA
* inhibits neprilysin, which degrades:
* ANP, BNP
* angiotensin II
* since angiotensin II degrades has the opposite effects as natriuretic peptides, the effects of administering sacrubitril alone cancer eachother out
36
sacubitril
- how is it given
- clinical uses
* usually given with valsartan, which blocks angiotensin II
* net effect is:
* enhanced effects of ANP, BNP
* blocked effects of Ang II
* clinical uses
* **chronic heart failure**
* **reduces mortality/hospitalization in patients with reduced EF**
37
adverse effects of sacutrabil and valsartan
* hypotension
* hyperkalemia
* renal impairment
38
what is ARNI?
combination of sacutiril + valsartan
39
contraindications of sacubitril + valsartan
* hypersensitivity
* angioedema
* all the contraindications of ARBS
* co- administration with RAS inhibitors
40
endothelin
* where is is synthesized?
* what can it do?
* ET-1 (endothelin) is made by endothelial cells
* ET-1 can either
* bind an ET8 receptor on endothelial cells to induce production of NO, PGI2 leading to --\> vasodilatoin
* bind an ETa/ET8 receptor on vascular smooth muscle cells to induce contraction, leading to --\> vasoconstriction
* this is its predominant role
41
effects of endothelins on the cardiovascular system
* CVS
* vasoconstriction
* positive ionotropism and chronotropism
* vascular and myocardial hypertrophy (ETa)
* bronchoconstriction
42
AEs of endothelins
* CV disorders (cardiac, vascular hypertrophy)
* renal disorders
* pulmonary disorders
43
* explain the role of endothelin in the pathophysiological process of pulmonary hypertension
* in a normal pulmonary artery, there is a balance maintained between the contracile/proliferation effects of endothelin (when ET1 binds to smooth muscle) and the relaxing effects/anti proliferation (when ET1 binds to a receptor on the endothelium inducing production of PGI2/NO2), such that the pulmonary artery remains normal
* in pulmonary arterial hypertension:
* balance is shifted so vasoconstriction/proliferation is pronounced and vasodilation/relaxation is minimal
44
classes of drugs used to treat **pulmonary arterial hypertension**
45
ETA antagonists
* indication
* MOA
* list the drugs that fall into this category
* indication: pulmonary arterial hypertension
* MOA: bind ETa receptors on _vascular smooth muscle_ inhibiting binding of ET-1, thus inhibiting contraction/proliferation
* drugs: **- entan**
* ****bosentan
* macitentan
* ambrisentan
46
adverse effects of ETa angtaonists
(**- entans**)
* headache
* flushing
* hypotension
* edema
* palpitations
* (can impair liver function if taken chronically, chronic uste must be monitored)
47
contraindications of ETa antagonists
pregnancy (teratogenic)
48
prostaglandins
* indication
* MOA
* list the drugs in this category
* used to treat pulmonary arterial hypertension (PAH)
* MOA: serve as endogenous prostaglandins that induce vasodilation/antiproliferation
* drugs: **- prost-**
* ****epo**_prost_**enol
* ilo**_prost_**
* te**_prost_**inil
* selexipag
49
PDE5 inhibitors
* indication
* MOA
* drug names (s)
* treatment of PAH
* MOA: inhibits PDE5, which metabolizes cGMP.
* thus, it maintains levels of PCK, allowing for vasodilation
* drugs: **-fil**
* ****tadal**_fil_**
* sildan**_fil_**
50
soluble gaunylate cyclase (sCG) stimulant
* MOA
* indication
* drug name
* use to treat PAH
* induces smooth muscle relaxation
* **riociguat**
51
calcium channel blockers
* indication
* MOA
* drug names
* treatment for PAH (amongst other things)
* MOA: impede contraction of smooth muscle --\> less vasoconstriction
* drugs
* **- dipine:** nifedipine, amlodipine
* diltiazem
