Hypertension - Sharpe Flashcards
What is the primary function of renin?
increase blood pressure
What does renin cleave?
cleaves angiotensinogen to form AngI
What increases renin release?
- loop diuretics
- ACE inhibitors
- ARBs
- renin inhibitors
(via disruption feedback)
What decreases renin release?
- NSAIDs
- beta blockers
Renin release regulation
- Renin release is regulated by beta 1 receptor activation
- Increased levels of Na sensed by the macula densa inhibits renin production and release
- Intravenal baroreceptor pressure increase = inhibits renin release
What does ACE do?
- forms AngII from AngI which occurs primarily in the lungs
Where are AT1Rs the strongest?
kidney
AT1R actions
- vasoconstriciton
- fibrosis
- VSMC inflammation
- oxidative stress
- cardiac hypertrophy
AT2R actions
- vasodilation
- antifibrotic
- anti-inflammation
- reduce oxidative stress
- antiproliferation
AngII actions n
- increase TPR -> increase BP
- increase cardiac contractility by opening Ca channels
- increase HR
- antidiuretic; increase Na reabsorption
- increase production and release aldosterone from adrenal cortex
- constricts renal vascular smooth muscle
What does ACEI’s do?
- keeps AngI from being converted to AngII -> lowers BP and enhances natriuresis
- Reduces TPR by arteriolar dilation and increase compliance of large arteries which reduces systolic pressure
ACEI drugs
- Benazepril
- Captopril
- Enalapril
- Fosinopril
- Lisinopril
- Moexipril
- Quinapril
- Ramipril
What are the categories of ACEI’s?
- Sulfhydryl-containing
- Dicarboxyl-containing
- Phosphorus-containing
Sulfhydryl-containing ACEI
Captopril
Dicarboxyl-containing ACEI
- Enalapril
- moexipril
- benazepril
- quinapril
- Ramipril
Phosphorus-containing ACEI
Fosinopril
What are the effects of ACEI’s?
- inhibits degradation of bradykinin
- increase levels of natural stem cell regulator
- increase renin prodction (due to loss of AngII feedback)
Who are ideal candidates for ACEI?
patients with elevates levels of plasma renin; they probably have too much AngII production because they have high levels of renin
Which patients are not ideal candidates for ACEI?
in patients with primary aldosteronism
Are ACEI’s a concern in patients who exercise or experience postural changes?
no
What can be combined with ACEI’s for additional management?
can be combined with thiazides or CCB for additional management
What does ARBs do?
blocks AT1R by binding to the AT1 receptor as a competitive antagonist but binding is almost irreversible
ARB drugs
- Azilsartan
- Candesartan
- Irbesartan
- Losartan
- Olmesartan
- Valsartan
- Telmisartan
What is a special thing about ARBs?
renoprotective for type 2 diabetics
What does CCB’s do?
block entry for voltage-gated calcium channels; inhibit calcium entry into smooth muscle such as cardiac myocytes; this will cause decrease in TPR and relief of the HTN
CCB drugs
- Amlodipine
- Felodipine
- Nifedipine
- Diltiazem
- Verapamil
What are the categories of CCB’s?
- Dihydropyridine
- Nondihydropyridine
Dihydropyridine CCB’s
- Amlodipine
- Felodipine
- Nifedipine
Nondihydropyridine CCB’s
- Diltiazem
- Verapamil
Dihydropyridine CCB’s effects
- Vascular smooth muscle effects are more than cardiac effects
- May have tachycardia initially
- Have predominant effect on vasodilation and afterload reduction; have less effect on the heart
Nondihydropyridine CCB’s effects
- Greater effects on cardiac myocytes and AV
- Have effects on both vasodilation and negative inotropy and chronotropy
CCB’s effects
- Blocking smooth muscle all over the body such as GI tract
- Decreases arterial resistance, blood pressure, and cardiac afterload
- Decrease contractility comes from cardiac myocytes causing negative inotropic effects
- Causes decrease pacemaker rate and AV node conduction velocity
- Are antianginal, antiarrhythmic, and antihypertensive
α1-blocker drugs
doxazosin
α1-blocker effects
- have effect on vascular smooth muscle
- Will decrease arteriolar resistance -> decrease TPR -> increase venous capacity -> decrease BP -> body will initially have a reflex to fix the BP and increase heart rate and renin activity but this eventually goes away and vasodilation stays keeping the BP down
What is added with α1-blockers?
Diuretic added with these medications because when BP drops, body will try to renally compensate -> retention of salt and water -> add diuretic to help offset the compensation
β-blocker drugs
- Atenolol
- Bisoprolol
- Carvedilol
- Labetalol
- Metoprolol tartrate
- Metoprolol succinate
- Propranolol
β1 receptor blockade effects
- Decreases stroke volume & heart rate -> decreased cardiac output
- Decreases renin release
- Partial agonist/intrinsic sympathomimetic activity: peripheral vasoconstriction, bronchoconstriction, hypoglycemia
- initial reaction -> decreased cardiac output and increased (reflexive) peripheral resistance
β2 receptor blockade effects
- Increased airway resistance
- Inhibit lipolysis -> can impair ability to cope with hypoglycemia
- Reduce intraocular pressure (used to treat glaucoma)
When do we reach lipolysis ?
- lipolysis: breaking down fat for energy
- when we haven’t eaten in a while or if you do heavy endurance activity; type I DM reach this fairly quickly
What is the β-blocker prototype?
- propranolol
- long acting form available
Which β-blockers are β1-selective?
- metoprolol
- atenolol
- nebivolol
Why are β1-selective blockers important?
- less respiratory issues
- less lipolysis issues
Which β-blockers also have some α1-blocker effects?
- labetalol
- carvedilol
Which β-blocker is the most β1-selective?
nebivolol
nebivolol actions
- Causes vasodilation via NO synthase activation
- Increases insulin sensitivity, no lipid effects
Central α2-agonist drugs
clonidine
Central α2-agonist effects
- Decrease SNS outflow
- Decrease peripheral NE
- Decrease heart rate & stroke volume (supine)
- Decrease vascular resistance (standing)
- If dose is too high, also agonize α2b receptors -> vasoconstriction
Where is the α2 receptor located?
brainstem
ACE inhibitors adverse effects
- hypotension especially on first dose for patients who have high renin levels
- dry persistent cough
- hyperkalemia
- angioedema
In ACEI’s, how is the dry persistent cough produced and what can you do to manage it?
- cause by accumulation of bradykinin / PG / substance P in the lungs
- ASA or iron supplements can reduce cough
- Can lower dose or switch to ARB
What is a contraindication for ACEI’s?
- pregnant women
- teratogenic
- can cause renal development issues in 3rd trimester
ARB’s adverse effects
Half the incidence of cough and angioedema compares to ACE inhibitors
What is a contraindication for ARB’s?
- pregnant women
- teratogenic
- can cause renal development issues in 3rd trimester
Which patients is most likely to experience hyperkalemia using ACEI’s?
patients on potassium supplements or potassium-sparing diuretics
Which patients is most likely to experience hyperkalemia using ARB’s?
patients with renal disease, on potassium supplements or potassium-sparing diuretics
CCB’s adverse effects
- Cardiac depression
- Flushing, fizziness, nausea (associated with exaggerated vasodilation)
- Peripheral edema (swollen ankles; gravitational problem)
- Constipation
- Can aggravate GERD
CCB’s adverse effects: cardiac depression
- bradycardia, AV block, cardiac arrest, heart failure
- Nondihydropyridine are going to be at greater risk of this
α1-blocker adverse effects
- Postural hyper/hypotension
- Risk of congestive heart failure (CHF) with doxazosin (monotherapy)
β-blockers adverse effects
- Peripheral vasoconstriction, Hypoglycemia, lipid abnormalities, Bronchoconstriction risk
- Can cause bradycardia; only worry in patients that already have bradycardia; fine to use in patients that have a normal heart rate
- Abrupt discontinuation leads to withdrawal syndrome
- Possible: fatigue, insomnia, nightmares, depression
What are possible withdrawal symptoms following the abrupt discontinuation of β-blockers?
- hyperglycemia
- vasoconstriction
If β-blockers cause impaired AV conduction, what is the patient at risk for?
bradyarrhythmia
Central α2-agonist adverse effects
- Postural hypotension
- Erectile dysfunction
- Nightmares/vivid dreams
- Bradycardia
- Withdrawal syndrome
What are possible withdrawal symptoms following the abrupt discontinuation of Central α2-agonists?
- headache
- tremors
- sweating
- tachycardia
Bradycardia is a problem in which patients taking a Central α2-agonists?
patients with AV dysfunction (disease or drug-induced)
Central α2-agonists poses a risk for which type of patients?
- for congestive heart failure patients
- due to decreased SNS tone to heart
- can worsen CHF
ACE inhibitors kinetics
- Eliminated primarily in kidney
- fosinopril and quinapril are equally both kidney and liver
- hydrolyzed in liver to active metabolite: enalapril, benazepril, fosinopril, quinapril, ramipril, moxepril
- fosinopril, quinapril, ramipril: absorption decreased by food (extent the same)
ARBs kinetics: Candesartan cilexetil
- Inactive prodrug hydrolyzed into active form in GI tract
- clearance is RENAL and hepatic
ARBs kinetics: Olmesartan medoxomil
- Inactive prodrug
- hydrolyzed into active form in GI tract
ARBs kinetics: Azilsartan medoxomil
- Inactive prodrug hydrolyzed into active form in GI tract
- Metabolized by CYP2C9 into inactive metabolites
ARBs kinetics: Losartan
- Converted to active metabolite by CYP2C9 and CYP3A4
- Clearance by liver and kidney
- Bonus MOAs—also a competitive antagonist of thromboxane A2 receptor (decreases platelet aggregation)
- metabolite decrease COX2 mRNA upregulation and PG production
ARBs kinetics: Irbesartan
Clearance is renal and liver, not affected by mild to moderate failure
ARBs kinetics: Telmisartan
Clearance mostly HEPATIC
ARBs kinetics: Valsartan
- Food decreases EXTENT of absorption significantly
- Clearance is HEPATIC
CCB’s kinetics
- CYP3A4—responsible for 1st pass metabolism of many CCB
- Bioavailability increased by CYP3A4 inhibitors (macrolides & imidazole antibiotics, antiretroviral agents, grapefruit juice
- Bioavailability reduced by CYP3A4 inducers (rifampin, carbamazepine, St. John’s wort)
- Verapamil—inhibitor of intestinal and renal P glycoprotein -> can increase levels of digoxin, cyclosporine, and loperamide
α1-blocker kinetics
- Long t1/2 (22h)
- Metabolized extensively by kidney and liver
β-blockers kinetics
- Half life is variable
- Lipophilic agents are more antiarrhythmic than hydrophilic agents
- Metabolized and eliminated by liver
- Metoprolol (most significant), carvedilol, nebivolol are CYP2D6 dependent
Which β-blockers is lipophilic?
- metoprolol
- bisoprolol
- carvedilol
- propranolol
Which β-blockers is hydrophilic?
- atenolol
- labetalol
