Anti-Hypertensives Flashcards
What factors stimulate increased secretion of Renin?
- Decreased macula densa intracellular NaCl (from NKCC2)
- Decreased afferent renal blood pressure (sensed by JG cells) -> inhibits prostaglandins
- Activation of beta-1 adrenergic receptors
Why do NSAIDs interfere with the RAA system?
Signalling for release of renin is done via prostaglandins
-> inhibition of synthesis will inhibit the pathway
What inhibits renin release?
When angiotensin 2 feeds back on an AT1 receptor (receptor for AT2)
What does ACE do and where is it located?
Cleaves Angiotensin 1 to Angiotensin 2, also catalyzes the degradation of bradykinin
Located on vascular endothelium of most organs, but especially lung and kidney
What are the three main effects of angiotensin 2?
- Increased arterial pressure
- Na / fluid retention
- Vascular and cardiac remodeling
How does angiotensin 2 affect blood pressure in the kidneys and peripherally in general?
Directly causes arteriolar and vasoconstriction, and constricts the efferent arteriole of the kidney, generally increasing or having mixed effects on the GFR
What is the effect of AT2 on the kidney?
Directly stimulates Na/H exchanger in proximal tubule, and also enhances aldosterone secretion
What is the effect of AT2 on cardiac / vascular remodelling?
Stimulates the migration, proliferation, and hypertrophy of vascular smooth muscle cells, as well as hypertrophy of cardiac myocytes. Promotes myocardial fibrosis through aldosterone.
Also increases preload (volume expansion) and afterload (greater peripheral resistance)
Give two important ACE inhibitors
Enalapril
Lisinopril
Why are ACE inhibitors important in chronic heart failure? What effect does this have on cardiac output and stroke volume?
Reduce preload and afterload, thus slowing the progress of ventricular dilation
This actually increases cardiac output and stroke volume in CHF
What affect does an ACE inhibitor have on GFR?
Tends to decrease GFR due to lack of constriction of efferent arteriole, which helps with proteinuria
What diabetic condition are ACE inhibitors good at treating?
Diabetic nephropathy
Give two important side effects of ACE inhibitors?
- Persistant dry cough
- Hyperkalemia (due to decreased aldosterone secretion) -> especially a problem in renal failure or if patient is on another K+ sparing diuretic
Why should NSAIDs not be used with ACE inhibitors?
Can precipitate renal injury due to decreased RBF, and cause hyperkalemia
When are ACE inhibitors contraindicated?
Pregnant patients -> teratogenic
What is the name of the renin inhibitor?
Aliskiren
What are the untoward effects of Aliskeren? Contraindication?
Mainly GI disturances and cough
Contraindicated in pregnancy
Give two angiotensin receptor (AT1) blockers: ARBs?
- Losartan
2. Valsartan
When are ARBs given? Contraindication?
In patients who develop ACE-inhibitor-mediated cough, since ARBs do not cause this
Contraindication is still pregnancy
What is the half life of an ACE inhibitor?
About 12 hours -> good for pairing with HCTZ or other K+ wasting diuretic
What is the neprilysin inhibitor and how does this work? Who is it used in?
Sacubitril
Inhibits neprilysin, which is responsible for cleavage of natriuretic peptides which have good effects.
Used in combination with valsartan for treatment of heart failure
Why are ACE inhibitors and ARBs good in acute myocardial infarction?
They reduce cardiac work
What are the four general effects of beta blockers that make them useful for management of cardiac conditions?
- Decreased cardiac excitability
- Antihypertensive effect
- Reduced inotropy
- Reduced cardiac remodelling (which is normally induced by longterm exposure to NE)
How do beta blockers reduce oxygen consumption by the heart?
They reduce the heart rate, allowing for increased filling time and stroke volume
Furthermore, they reduce the inotropy of the heart, resulting in less forceful contractions
How do beta blockers protect against arrhythmias?
Slowing of conduction velocity and increasing refractory period in atrial muscle and the AV node
-> this reduces the risk of supraventricular tachyarrhythmias escaping into the ventricles (i.e. atrial tachycardia)
How do beta-blockers work as an anti-hypertensive?
Blocking of beta-1 receptors in the JGA will greatly downregulate renin release
When are beta-blockers used as a monotherapy for hypertension?
In more complicated hypertension, where there is a co-morbidity responding to beta blockade: i.e. hyperthyroidism, migraine, angina, congestive heart failure, or MI
Why are all beta-blockers contraindicated in asthma?
Because beta-blockers all tend to undergo extensive CYP450 first pass metabolism, even cardioselective beta-blockers (i.e. A-BEAM) have the potential to antagonize beta-2 receptors depending on the patient’s degree of metabolism
Beta1 blockers are selective but not specific
Why might atenolol be used rather than metoprolol?
It does not undergo first pass metabolism
Both are beta-1 selective
What beta-blockers are not recommended in MI?
Acebutolol and pindolol -> beta-blockers with intrinsic b1 sympathetic agonist activity (do not want to stimulate the heart)
What is a unique side effect of labetalol?
Because of it’s alpha1-blocking activity, it can cause orthostatic hypertension
It is used to manage hypertension in pregnant patients
How is carvedilol metabolized, and why is it great for heart failure?
Via CYP2D6
Great for heart failure due to inhibition of oxygen radical mediated lipid peroxidation and vascular smooth muscle mitogenesis
What is sotalol and its primary indication?
A non-selective beta-blocker (like propanolol), but also is a potassium-channel blocker in the heart, delaying repolarization.
-> effective anti-arrhythmic drug by slowing repolarization
When is esmolol given?
It is a short-acting beta 1 blocker (half-life 10 minutes) given IV in emergency situations to control arrhythmias, acute hypertension, and myocardial ischemia
What are the two primary side effects of concern for beta blockers?
- CNS effects
- Hypoglycemia / dyslipidemia (blocking of beta-2/beta-3 effects)
- > a diabetic patient could only tell they have hypoglycemia via sweating on palms (muscarinic), all other signs would be absent
What is the I-funny channel blocker and how does it work?
Ivabradine
Blocks the channel in pacemaker cells, especially the SA node which is activated by hyperpolarization, and leads the pacemaker cells to spontaneously depolarize and allow calcium inside
If channel is a nonspecific channel (lets Na+ and K+ flow)
When is ivabradine indicated?
Patients who are at max dose of beta-blockers and still have a heart rate >70
What are the common side effects and contraindications of ivabradine?
Atrial fibrillation and visual disturbances.
Visual disturbances are due to enrichment of If channels in the retina.
Contraindication is: pregnancy (teratogenic)
What is the mechanism of action of methyldopa?
Alpha-2 agonist, like clonidine.
It is a dopamine derivative which is made into methylnorepinephrine
Reduces sympathetic tone throughout the body
What is methyldopa indicated for, and what is its common side effect (other than CNS effects)?
Indicated for hypertension, especially treatment of hypertension during pregnancy (like labetalol)
Hemolytic anemia (lupus according to sketchy??)
What are alpha-1-antagonists typically combined with for treatment of hypertension?
Diuretics or beta blockers
-> not good as monotherapy
What is the primary calcium channel in the heart?
The L type calcium channel, also called slow channel
What are the two categories of calcium channel blockers?
- Dihydropyridines
2. Non-dihydropyridines
What is the mechanism of action of dihydropyridines?
They bind the L type Calcium channel in its open state, slowing calcium entry when it’s open, but not delaying its closure.
Dihydropyridines are vasoselective (rather than cardioselective), and prevent vascular smooth muscle contraction
How do dihydropyridines affect preload?
They have no effect on it -> do not cause vasorelaxation. Will also not be associated with orthostatic hypertension
What are the dihydropyridines of significance?
- Nefedipine
2. Amlodipine
Why is amlodipine typically given over nefedipine?
Nefedipine has a short half-life, and thus often induces a rapid hypotension and reflex tachycardia, causing MI
-> must be given in timed-release form
Amlodipine has a much longer half-life and does not cause this baroreceptive reflex
What does amlodipine reduce mortality in?
Patients with left ventricular dysfunction / heart failure
-> reduction in afterload
What are the common side effects of dihydropyridines?
Flushing and peripheral edema (pitting edema of the ankles)
What are the non-dihydropyridine calcium channel blockers?
- Verapamil
2. Diltiazem
What is the mechanism of action of the non-dihydropyridine VGCC blockers?
They bind to the L type Calcium channel, but are cardioselective and will bind to both the open and inactivated form.
They reduce inward calcium current and delay channel closing, reducing the chronotropy and inotropy of the heart.
There is only minor blockage of L-type calcium channel on arteries
What are non-dihydropyridines used to treat and why?
Angina -> reduce cardiac work by reduction of inotropism
Supraventricular tachycardias -> delayed AV node conduction
Antiarrhythmia in general
What is the important contraindications of nonDHPs?
Heart failure -> reduction in cardiac contractility and cardiac block.
Verapamil can also cause hypotension due to alpha-1 blocking effects
AV block -> reduction in conduction
Also, should not be used with beta-blockers due to increased suppression of conduction
What is an important drug interaction with verapamil?
Decreases digoxin’s renal clearance -> need to lower digoxin’s dose or will be toxic
Why are beta-blockers always given with direct arterial vasodilators?
Otherwise, will cause reflex tachycardia and increase in renin secretion (beta1-antagonism will counter this)
What are the direct vasodilators?
- Hydralazine
- Minoxidil
- Sodium Nitroprusside
What is the mechanism of hydralizine and why is it not commonly given anymore? When is it given?
Mechanism unknown, relaxes arteriolar smooth muscle to reduce preload.
Not commonly given due to lupus-like syndrome.
Now given to patients who cannot handle standard therapy for heart failure (ACE + beta blocker + loop diuretic) in combination with a nitrate to reduce both preload and afterload
What is the mechanism of action of minoxidil? How does this relate to its contraindication?
Activates ATP-modulated potassium channel in smooth muscle, causing hyperpolarization and arteriolar relaxation
Contraindicated in patients with LV hypertrophy and diastolic dysfunction, as increased preload may lead to heart failure + pulmonary hypertension
What is minoxidil used for and given in combination with?
Used for complicated hypertension which is poorly responsive to other agents
Given in combination with a loop diuretic (less pulmonary congestion) and beta blocker (less increased cardiac output from preload)
What is the primary side effect of minoxidil and how has this been used?
Causes hypertrichosis (excess hair), bad in females, but good in bald males -> marketed as "Rogaine"
What is the mechanism of action of sodium nitroprusside? What does it do to heart rate?
Generates nitric oxide, causing both venous and arterial relaxation, and a subsequent decrease in preload and afterload
Actually causes increase in heart rate
How does sodium nitroprusside affect cardiac output in normal vs LV dysfunction individuals?
Normal: Reduces cardiac output (decreased preload)
LV dysfunction: Increases cardiac output (decreased afterload, preload affects are not as important since heart is already working suboptimally)
What is nitroprusside used for?
Treatment of hypertensive emergencies such as acute aortic dissection (along with beta-blocker to reduce heart rate) or cardiogenic shock due to massive MI or rupture of papillary muscle
-> situations when both decreased preload and afterload are needed
Also, controlled hypotension in patients under surgical anesthesia
What is the relative half life of nitroprusside?
Very short, on the order of 2 minutes, given IV
What is the main untoward effect of nitroprusside?
It is metabolized to cyanide and then nitric oxide. Long-term high doses will lead to cyanide accumulation -> lactic acidosis
Liver normally detoxifies cyanide to thiocyanate
