Antihypertensives Flashcards
What is angiotensinogen
a plasma glycoprotein which is synthesized in many organs, includingliver, kidney, brain, and fat. It is the only known substrate of renin
What is renin
a protease synthesized and stored in the renal juxtaglomerular apparatus.
What is angiotensin I (Ang I)
a decapeptide formed by proteolysis of angiotensinogen by renin.Has weak vasoconstrictor activity
angiotensin II (Ang II)
an octapeptide formed by proteolysis of Ang I by angiotensinconverting enzyme (ACE). A very potent vasoconstrictor.
angiotensin converting enzyme (ACE)
a peptidase located in several tissues, althoughthe highest levels are found in lung epithelial cells, which are considered the major
source of circulating Ang II.
angiotensin III (Ang III)
a heptapeptide formed by the action of an aminopeptidase onAng II; has less vasoconstrictor activity than Ang II.
angiotensin receptors
there are two classes of angiotensin receptors: AT1 and AT2. All known postnatal physiological effects of angiotensin appear to be mediated by AT1
receptors.
AT1 receptors
Angiotensin 2 is ligand G protein coupled receptors. IP3/DAG cascade
Release of calcium - vasoconstrictor activity
Mitogenic activity - stimulate growth
Clinical target
AT2 receptor
G protein coupled - activate phosphodiesterase
High expression in fetus
Postnatally their function is unknown
Not a clinical target
bradykinin
a peptide with potent vasodilator activity. While not part of the renin-angiotensin system, it is a substrate for ACE, which converts bradykinin to an inactive fragment
Opposite effect of angiotensin
Bradykinin gets broken down by ACE
How does ang II effect the blood pressure
blood pressure:
intravenous infusion of Ang II produces a strong pressor responsewithin 10-15 seconds. The pressor response is primarily due to vasoconstriction of vascular smooth muscle mediated by angiotensin receptors on the muscle cells.
-Resets the baroreceptors ( no reflex Brachy or tachy)
How does ang II effect adrenal cortex
adrenal cortex: Ang II acts directly on the zona glomerulosa of the adrenal cortex to stimulate aldosterone biosynthesis and release, which in turn increases renal sodium
reabsorption and blood volume.
How does ang II effect the CNS
central nervous system:
Ang II exerts a CNS- mediated pressor response caused by increased central efferent sympathetic activity to the periphery.
Aka - increase NE release from ANS
It also stimulates thirst (dipsogenic effect)
the secretion of vasopressin and ACTH.
- increase vasopressin release -> increase. H20 reabsorption
How does ang II effect cell growth
cell growth: Ang II exerts mitogen activity for vascular and cardiac muscle cells, andmay contribute to cardiac hypertrophy.
- cardiac remodeling and HF
- fetal growth ( AT1)
What is the rate limiting step in renin secretion
Renin release is the rate-limiting step in the formation of Ang II, and can be controlledby either local renal mechanisms or through the CNS:
What do renal vascular receptors do for regulation
renal vascular receptor: functions as a stretch receptor, and reductions in stretch
caused by a decrease in renal perfusion pressure leads to increased renin release
Decrease stretch -> increase renin release
What does macula densa do for regulation of renin
b.) macula densa: receptors here are sensitive to rate of sodium delivery to the distal
tubule; reductions in sodium delivery stimulate renin release
How does the sympathetic nervous system regulate renin release
c.) sympathetic nervous system: norepinephrine stimulates renin release via direct action on β-adrenergic receptors on the juxtaglomerular cells
How does ang II regulate renin release
d.) angiotensin II: Ang II acts on juxtaglomerular cells to reduce renin release, forming a short-loop negative feedback system.
What are the four points of intervention for renin ang system
- renin release : ⬇symp output ⬇release
- formation of Ang I by renin (renin inhibitors): no more effective and induces reactive renin release
- formation of Ang II by ACE (ACE inhibitors) : ang II is blocked
(-pril) - AT1 receptors (AT1 receptor antagonists)
What are the three classes of ace inhibitors
Class 1 - Captopril - active by its self (-SH) sulfhydro group
Class 2 Pro drugs
- enalapril ➡enalaprilat
Liver metabolism
Class 3 - lisinopril - active drugs
More water soluble longer half life
Actions of ace inhibitors
⬇BP by ⬇ TPR
Ace inhbs don’t induce sympathetic reflex ( ok for ischemic heart disease)
⬆Bradykinin bc ace also breaks down bradykinin
- symptoms skin rash and dry cough
When do you use ace inhibitors
All states of heart failure ( ⬇mortality)
HTN ( dont impair insulin sensitivity so
Side effects of ace inhibitors
Hyperkalemia - ⬇ in aldosterone release Hypotension Renal failure due to ⬇ BP Angioedema - very rare Teratogenic Skin rash - ⬆bradykinin Most common Dry cough -⬆ bradykinin. Most common
Side effects with captopril
Loss of taste
Neutropenia
Oral lesions
In addition to the others for all ace inhibitors
What are contraindications of ace inhibitors
Pregnancy
Bilateral renal stenosis ( need high systemic BP to press blood into the kidneys)
Hyperkalemia
Severe renal failure ( won’t be able to perfuse kidney)
Angiotensin receptor antagonists
-All end in -sartan
-They avoid bradykinin mediated side effects
-don’t inhibit AT2 receptor effect
(losartan, valsartan)
- orally active
- not superior to ace inhibitors
There are four sites of control for blood pressure:
arterioles (resistance),
venules capacitance),
heart (pump output),
and kidney (volume)
Treatment for HTN - step 0
Lifestyle changes ⬇Na intake ⬆Exercise ⬇Smoking ⬇Alcohol
HTN treatment step 1 - diuretics
diuretics- lower blood pressure by increasing Na+ excretion and thus reduce bloodvolume -> ⬇preload ->⬇co
HTN treatment step 2 - agents that alter sympathetic nervous system function
- lower blood pressure by reducing peripheral vascular resistance, reducing cardiac function, and increasing
venous pooling in capacitance vessels
HTN treatment step 3 direct vasodilators
lower pressure by relaxing vascular smooth muscle increasing capacitance
⬇TPR
HTN treatment RAAS inhibitors
⬇TPR
⬇Blood volume ➡⬇preload
Thiazide diuretics - what do they do and use
⬇Na reabsorption in the dct
Low ceiling diuretics
Classic example : hydrochlorthiazide
Increase urine output 3 x
Use: HTN 1st line for mild HTN
Chef when edema is mild
Osteoporosis - ⬇urinary calcium loss
Thiazide diuretics - side effects
Side effects : hypokalemia
Hypomagnesia
Hyperglycemia - k channels play a role in insulin channels in pancreas
Loop diuretics - what are they, uses
Furosemide and ethacrynic acid, bumetanide, torsemide
⬆8 x urine output high ceiling diuretics
( pee like a race horse)
Use :
Chf- when edema is real bad
HTN - lower doses than w. edema
K sparing diuretics side effects, uses , what are they
spironolactone/ eplerenone - aldo recept antagonist
amiloride/ triamterene. - inhibit ENac
Not as good as loop diuretics
⬇Na intake
Use Chf ( spironolactone or eplerenone )
Side effects
Hyperkalmia
Metabolic acidosis ( not common)
spironolactone- gynecomastia or impotence in males
Side effects of loop diuretics
Side effects Hypokalemia Ototoxicity - ringing in ears reversible Hyperglycemia Hyperuricemia
Aquaretics
inhibit the vasopressin V2 receptors, which promote the synthesis
and translocation of aquaporin-2 (AQP2) in the collecting duct. When AQP2 is present, water is retained and the urine becomes more concentrated; when it is absent, water isnot retained, and the urine becomes more dilute and urinary output is increased. In
addition, plasma Na+ levels rise.
conivaptan and tolvaptan. Conivaptan is amixed V1 and V2 antagonist and it delivered IV, while tolivaptan is an oral V2
antagonist. The major clinical use of these two compounds is to treat hyponatremia.
β1-adrenergic receptor antagonists (β-blockers)
Used for mild HTN
- ⬇hr
- ⬇inotropy
- ⬇renin release
propanolol, metoprolol, atenolol
β1-adrenergic receptor antagonists (β-blockers)
Side effects
Side effects ⬇Cardiac function Bronchoconstriction ( beta 2) bc it's not super selective CNS: sedation (propranolol ) Metabolic effects: Hyperglycemia ⬆Tg ⬇Hdl
Rebound hypersensitivity
- upregulation of beta receptors on the end organ so can’t abruptly remove pt from beta blockers
α1-adrenergic receptor antagonists (α-blockers)
prazosin, terazosin, doxazosin
Vasodilators - ⬇TPR and ⬇preload
Don’t have metabolic side effects
Orthostatic hypotension ( first day)
Only use alpha 1 selective
Central adrenagric inhibitors
Clonidine( alpha 2 agonist)
⬇NE release
Reserpine - deplete NE - ⬇NE release
Methyldopa - never will use
Direct vasodilators
Relax smooth muscle ⬇TPR ⬆Venous capacitance Might get reflex tachycardia Not first line therapy but as an adjunct therapy with something
Calcium channel blockers
Verapamil , diltiazm, DHP
No reflex tachy b( v and d) bc neg inotropy
DHP does have a risk of reflex tachy
K channel openers
Hydralazine, minoxidil ( rogaine)
Vasodilators
Arterial dilator
Not used anymore for HTN treatment
How do you choose the treatment of HTN ??
Start with best initial drug - depends on pt
Diabetics : avoid beta blockers and high dose diuretic/ use acei
dyslipidemias : avoid beta blockers and diuretics / alpha may help
Old ppl - everything is good in low doses
Angina - avoid reflex tachy ( DHP, acei, arb)
Post mi - b blockers , acei and arb - preferred stop remodeling
Sympatholytics that treat HTN
β1-adrenergic receptor antagonists (β-blockers)
α1-adrenergic receptor antagonists (α-blockers)
central adrenergic inhibitors
