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S2B5 Pharmacology > Vasoactive Peptides & Inhibitors > Flashcards

Vasoactive Peptides & Inhibitors Flashcards

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)
  • angiotensin I converted to angiotensin II
    • angiotensin II inhibits renin release
  • antiogensin II –> III –> IV
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2
Q

antiotensin II receptors

  • where are they found?
  • what does stimulation by angiotensin cause?
A
  1. 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
  1. AT2 receptors
  • found in fetal tissues
    • angiotensin II binding maintains healthy tissues
  • possibly found on endothelium and involved in NO mediated vasodilation
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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
  • kidney: aldosterone release
    • rentention of Na+ and fluid
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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)
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5
Q

list the classes of drugs that inhibit angiotensin II’s pathological effects

A

= inhibition of RAAS system

  1. renin inhibitors: inhibit conversion of antiotensinogen to angiotensin I
  2. ACE inhibitors: inhibit conversion of angiotensin I to angiotensin II
  3. AT receptor blockers
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6
Q

what three factors can increases renin release?

A
  • drop in tubular NaCl
  • low blood pressure
  • stimulation of B1 receptors
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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_
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8
Q

ACE inhibitors MOA

A

ACE inhibitors

  1. inhibit conversion of angiotensin I to angiotensin II
  2. 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
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9
Q

AEs seen in ACE inhibitors but not ARBs

A

can cause a persistent dry cough - this is due increase in bradykinin

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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
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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
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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
  • reduce risks of type 2 diabetes
    • increase insulin sensitivity?
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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
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14
Q

what are the ACE inhibitors?

A

“prils”

captopril, lisonopril

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15
Q

what are the AT1 Receptor blockers (ARBs)?

A

“sartans”

losartan, valsartan

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16
Q

what renin enzyme inhibitor did we discuss?

A

aliskiren

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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
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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
    • increase selecitivty of filtering membrane
      • such that growth factors are not leaking out into filtrate, damaging mesangium
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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

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20
Q

use of aliskiren

A

(renin enzyme inhibitor)

use = hypertension (not the first line though)

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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

S2B5 Pharmacology (3 decks)

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