Pharmacological Options in Heart Failure Flashcards
how is the SA node of the heart innervated/controlled
- B1(B2) adrenergic receptors (increase rate)
- M2 cholinergic receptors (decrease rate)
how is the atrial muscle of the heart innervated/controlled
- B1(B2) adrenergic receptor: increase force
- M2 cholinergic receptor: decrease force
how is the AV node of the heart innervated/controlled
- B1(B2) adrenergic receptor: increase automaticity
- M2 cholinergic receptor: decreased conduction velocity
M2 cholinergic receptor: AV block
how is the ventricular muscle of the heart innervated/controlled
- B1(B2) adrenergic receptor: increase automaticity and increased force
how are blood vessels innervated/controlled (coronary, muscle, viscera, skin, brain, erectile tissue, salivary glands, cerebral) and veins
what are the mechanisms to control smooth muscle
1. contraction:
- alpha 1 (G-protein coupled)
- stimulates phospholipase C and enhances Ca entry and intracellular Ca release
- causes contraction
2. relaxation:
- B2 (G-protein) receptor coupled to adenylate cyclase which increases cAMP
- cAMP stimulates protein kinase A and triggers phosphorylation cascade which will inhibit contraction
how do alpha 1 receptors respond to noradrenaline stimulation in vascular smooth muscle cell
- stimulation causes direct entry of Ca
- increases IP3 which stimulates the sarcoplasmic reticulum to increase more Ca
- Ca causes contraction of smooth muscles
how do B2 receptors respond to noradrenaline stimulation in the vascular smooth muscle cells
- linked to adenylate cyclase which stimulates cAMP
- cAMP causes phosphorylation cascade
- inhibitory effect on contraction
how do B1 receptors on the cardiac muscle cell respond to noradrenaline
- linked to adenylate cyclase which stimulates cAMP
- cAMP stimulates protein kinase A which will increase intracellular Ca
- Ca increases contractility
what does inotropy mean
force of contraction of heart
what does chronotropy mean
speed of contraction
what does lusitropy mean
diastolic relaxation of ventricles
what are the approaches to treatment in heart failure
- stimulate the heart
- offload the heart
- inodilators
what are sympathomimetics and what is their function
B1-agonists
stimulate adenylate cyclase via a G-protein to:
- increase cAMP 2. increased Ca 3. increased contraction
what substances act as sympathomimetics
- all catecholamines stimulate B-receptors
- dobutamine: synthetic B1 agonist
what are the effects of catecholamines and what are they used for
stimulate B receptors and also alpha receptors
cause –> vasoconstriction, increased HR, pro-arrhythmic
used in resuscitation, not for heart failure
what is dobutamine, what are its effects and how is it used
synthetic B1 agonist
- potent positive inotrope, little effect on heart rate, little effect on BP
2. indicated in life threatening heart failure with severly impaired systolic function
- short term treatment –> up to 3 days (residual benefit)
down regulates B-receptors
*monitor BP, HR, rhythm
what are diuretics and
substance that promotes production of urine (increase excretion of water and (electrolytes))
what is diuresis
increased urine flow
what is natriuresis
increased Na+ excretion
what are the classes of diuretics (5)
- loop
- thiazide
- potassium sparing (aldosterone antagonists, amiloride)
- osmotic
- carbonic anhydrase inhibitors
when are diuretics used
treatment and control of systemic edema from either cardiac, hepatic & renal glomerular disease
all patients with signs of congestive heart failure should receive a diuretic (only exception is cardiac tamponade)
what are the functions of loop diuretics
secreted into PCT, act in thick ascending limb loop of Henle
inhibits Na/K/Cl carrier in the lumenal membrane by combining with the Cl binding site –> causing loss of these ions, with water, in the urine
also induce renal prostaglandin synthesis (dilate vessels) –> increase renal blood flow (increase amount of filtration)
what is an example of a loop diuretic
furosemide
why are loop diuretics classified as high ceiling
Na/K/Cl carrier is responsible for reabsorption of a high proportion of Na in the tubular fluid
capable of causing excretion of 15-20% of filtered Na (normally around 1% excretion)
large increase in urine output
why is dose control essential in loop diuretics
because they are so potent
what are the side effects of loop diuretics
dehydration, pre-renal azotemia, electrolyte disturbances (esp. K, Na, Mg), ototoxicity (at very high doses or when used in combo with aminoglycosides)
what is the onset of action and duration of action of loop diuretics
1-1.5hours PO (well absorbed)
lasts 4-6 hours
onset is 10-20mins
where is the action of thiazides
secreted in PCT and DCT
what is the action of thiazides
block Na/Cl reabsorption causing loss of Na, H, K, Mg, Cl with water in the urine
what is the mechanism of thiazides dependent on
renal PG production
what is the potency of thiazides and what can make them ineffective
mild-moderate
ineffective if renal blood flow is low
what is the onset, duration of action and absorption of thiazides
slower onset
longer acting than furosemide
good oral absorption
what are the side effects of thiazides
as for furosemide
alkalosis
insulin resistance
what class of diuretics is amiloride
K sparing diuretic
where does amiloride act
collecting tubule
what is the action of amiloride
block lumenal sodium channel
indirectly decrease K loss
what is the potency of amiloride and when is it used
weak
used in combo with others to help to reduce hypokalemia
what class of diuretic is spironolactone
K sparing diuretic
what is the mechanism of action of spironolactone
aldosterone antagonist (competitive)
aldosterone: part of RAAS which acts of distal tubules/collecting ducts to increase reabsorption of ions and water –> conserves Na/secretes K+ –> water retention, increased blood pressure and volume
when is spironolactone used
weak diuretic –> in combo with others to reduce hypokalemia
to counter aldosterone escape
what is the safety profile of spironolactone
no apparent adverse effects in dogs (except reversible prostatic atrophy)
skin reactions in cats
where do osmotic diuretics act
filtered and effective mainly in PCT + loop
what is an example of an osmotic diuretics
mannitol used as 10-20% solution i.v (poor GI absorption)
where do carbonic anhydrase inhibitors act
secreted into PCT
what is the mechanism of action of carbonic anhydrase inhibitors
inhibit tubular production of H+ for Na/H exchange
leads to increased NaHCO3 and water (and K) excretion
what are carbonic anhydrase inhibitors used for
topically for glaucoma
what are the aims of vasodilators
- decrease preload
- decrease afterload
overall: reduce the cardiac workload (arterio-dilators, balanced vasodilators, venodilators)
what are the main classes of vasodilators
- calcium channel blockers
- alpha1 adrenoreceptor antagonists
- nitrates
- angiotensin inhibitors
what is the mechanism of action of calcium channel blockers
block L-type calcium channels
voltage operated channels responsible for Ca entry during depolarization
initiates contraction
if blocking will inhibit contraction
what is the cardiac sub-type of calcium channel blockers
phenylalkylamines (verapamil) –> cardiac effect
what are the vascular effect calcium channel blocker
dihydropyridines (amlodipine) –> vascular effect, primarilty arteriolar dilation, little cardiac effect
what are benzothiazepines
ex. diltiazem
calcium channel blocker
what are the pharmacokinetics of almodipine (bioavailability, metabolism, half life, Vd, safety)
- 90% bioavailability
- extensive metabolism
- long half life (around 30 hours)
- high Vd (25L/kg)
- good safety profile
what is an example of a1-adrenoreceptor antagonists
prazosin
what is the mechanism of action of prazosin
non-selective a1-antagonist
what are the pharmokinetics of prazosin (absorption, half life)
well absorbed
short half life –> 3-4 hours (give freq)
what are the side effects of prazosin
hypotensive effect prolonged
syncope
when is prazosin indicated
anti-hypertensive
what are nitrovasodilators and what are they used for
nitrates
short term antihypertensive therapy
what is the mechanism of action of nitrovasodilators
nitrates act as donors of nitric oxide
mimic endogenous system –> endothelium derived nitric oxide (lots of stimuli, shear stress/friction in blood vessels) –> diffuses to underlying vascular smooth muscle cell and activates guanylate cyclase –> cGMP –> relaxation
what are the side effects of nitrovasodilators
hypotension
how is nitrovasodilators given
ointment
caution to individual applying (wear gloves)
what are angiontensi II inhibitors
ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II
angiotensin II inhibitors act on the ATI receptors (AT1 subtype receptor antagonists)
what are the effects of angiotensin II
- vascular growth: hyperplasia, hypertrophy
- vasoconstriction: direct, via increased noradrenaline release from sympathetic nerves
- salt retention: aldosterone secretion, tubular Na reabsorption
what are the pharmocodynamic effects of ACE inhibitors
- arteriolar and venodilation
- decrease plasma aldosterone
- enhanced Na and water excretion
- reduced edema
- enhanced bradykinin vasodilation
what are the effects of angiotensin II and the kidney
angiotensin II increases glomerular filtration by constrictining the efferent and afferent arterioles (constricts efferent more –> increase the pressure within the glomerulus)
consequence of heart failure –> renal hypertension
ACE inhibitors will negate these effects
what are the side effects of ACE inhibitors
- hypotension
- renal impairement: monitor renal function & electrolytes
- hyperkalemia
- anorexia, diarrhea, vomitting, cough
how are ACE inhibitors administered
as pro drugs
enalaprin –> enalaprilat
benazepril –> benazeprilat
ramipril –> ramiprilat
imidapril –> imidaprilat
how are ACE inhibitors eliminated
renal/hepatic
what can decrease bioavailability of ACE inhibitors
food (enalapril, imidapril)
what are angiotensin II receptor antagonists
direct action at angiotensin II receptors
used in human cardiology
what are the differences between ACE inhibitors and angiotensin II receptor antagonists
block all formed by other routes
do not prevent breakdown of bradykinin
what is telmisartan (semintra)
angiotensin II receptor antagonist
competitive antagonist of the AT1 receptor
what does telmisartan (semintra) cause
- decreased BP
- decreased proteinuria
what are the side effects of telmisartan (semintra)
- hypotension
- decreased RBC count
what are the pharmacokinetics of telmisartan (semintra)
oral solution
high ppb
glucuronidation occurs (even in cat) but mainly excreted unchanged in feces
what is aldosterone escape
aldosterone may increase in incomplete inhibition of ACE
block with concurrent aldosterone antagonism –> spironolactone (beware hyperkalemia)
what are mechanism of action of inodilators
B1 agonists –> stimulate AC via a G-protein
phosphodiesterase (PDE) III inhibitors prevent breakdown of cAMP
both increase cAMP –> increased Ca –> increased contraction
what are examples of bipyridine compounds
amrinone, milrinone
what is the mechanism of action of bipyridine compounds
PDE III inhibitors
positive inotropes and vasodilators –> inodilators
what are the side effects of inodilators
ventricular arrhythmia
ruptured chordae tendinae
what is the mechanism of pimobendan
calcium sensitizers: sensitizes myocardium to Ca
inodilator: PDE III inhibitor effects
what are the benefits of pimobendan
less arrhythmogenic than bipyridine compounds
mild positive chronotropic effect
decreased sympathetic drive
what is the absorption of pimobendan impaired by
food
what are other effects of pimobendan
- PDE V inhibition (pulmonary)
- cytokine modulation
- antiplatelet effects
- positive lusitropic effect
