Cardio Pharm Flashcards
What is heart failure?
inability to provide required physiological needs
What is congestive heart failure?
- retention of fluid secondary to heart failure
- Na+ retention, H20 follows
- “diastolic failure”
What neurohumoral factors are increased in response to decreased perfusion of tissues in heart failure?
- SNS
- RAAS
- ADH
What are the adaptive responses that occur after an increase in neurohumoral factors?
- vasoconstriction
- Na/H2O retention
- increased inotropy
What maladaptive responses occur in heart failure?
- increased afterload
- increased cardiac work
- decreased cardiac efficiency
- fibrosis
- altered signaling
What is the goal of cardio pharm?
blunt maladaptive responses the best we can
What are 2 consequences of maladaptive responses in heart failure?
- decreased ventricular compliance
- decreased systolic function
What are the three types of CHF?
- left sided CHF: pulmonary edema
- right sided CHF: ascites
- biventricular failure: ascites, pleural effusion
How do you progress from heart failure to CHF?
- reduction in compliance of ventricle
- diseased heart fills at elevated pressure
What are the three goals of pharmacologic therapy for CHF
- resolve/prevent retention of fluid
- improve quality of life
- improve prognosis
How will cardio pharm improve the quality of life in CHF patients?
- improve hemodynamic parameters
- increase exercise capacity
How will cardio pharm improve prognosis in CHF patients?
decreased morbidity and mortality
What is preload?
end diastolic pressure
What is afterload
end systolic pressure
What drugs decrease preload?
- diuretics
- venous vasodilators
How do diuretics decrease preload to treat heart failure?
decrease plasma volume
How do venous vasodilators decrease preload to treat heart failure?
increase vascular volume
What drugs decrease afterload to treat heart failure?
arterial vasodilators
How do arterial vasodilators decrease afterload to treat heart failure?
decrease systemic vascular resistance
What drugs increase pumping strength/efficiency (positive inotropy) in treatment of heart failure?
- catecholamines (epi and norepi)
- phosphodiesterase inhibitors
- calcium sensitizers
- cardiac glycosides
Where are loop diuretics secreted?
into the tubular lumen
What is the MOA of loop diuretics?
- inhibition of Na/K/2CL symporter in the thick ascending LOH
- Na/K/ Cl remain in tubule, disrupting countercurrent multiplication
What is the onset of action of loop diuretics?
rapid
What is the duration of action of loop diuretics?
relatively short
Because loop diuretics can secrete lots of Na, it is considered potent or what?
high ceiling
Describe the potency of torsemide compared to furosemide
10x more potent, lasts longer –> be cautious of dehydration
When does peak diuresis occur after oral administration of furosemide?
1-2 hours
When does furosemide effect begin to dissipate?
6 hours
When does diuretic resistance begin to develop in healthy dogs after beginning furosemide therapy?
14 days
What factors contribute to furosemide resistance?
- increased expression of co-transporters in response to aldosterone like substance
- high ceiling diuretic
What effect does furosemide have when administered IV?
venodilation prior to onset of diuretic action
What are the adverse effects of furosemide?
- hypokalemia, hypochloremic metabolic alkalosis
- dehydration
- ototoxicity in humans
Furosemide also induces notable excretion of what two compounds?
Ca and Mg
What substances may blunt the furosemide response?
NSAIDs and steroids
What class of loop diuretics is torsemide in?
pyridine-3-sulfonylurea
When does peak diuresis occur with torsemide?
1-2 hours after oral administration
When does torsemide begin to dissipate?
12 hours
When is torsemide used?
when furosemide resistance develops
What are the adverse effects of torsemide?
- hypokalemia, hypochloremic metabolic alkalosis
- dehydration
Explain the activity of torsemide in regards to aldosterone.
anti-aldosterone activity
What is the MOA of thiazide diuretics?
- directly inhibit Na/Cl cotransporter in DCT
- Na, Cl, and H2O remain in tubule
Are thiazide diuretics considered high or low ceiling?
low
When does peak diuresis and dissipation occur with thiazide diuretics?
- rapid GI absorption
- peak diuresis 1-2 hours after oral admin.
- dissipates over 6-12 hours
Thiazide diuretics can be used synergistically with what other type of diuretic?
loop diuretics
What are the adverse effects of thiazide diuretics (more likely when used with loop diuretics)?
- hypokalemia
- dehydration
What effect do thiazide diuretics have on Ca?
relative Ca-sparing effect
What two drugs are thiazide diuretics?
- hydrochlorothiazide
- chlothiazide
What is the K sparing diuretic?
spiranolactone
What is the MOA of spiranolactone?
- antagonized effects of aldosterone
- decrease Na/H2O resorption in DCT/CT
- reduction in luminal Na channel
- reduction in Na/K ATPase pump at basolateral membrane
Is spironolactone a weak or strong diuretic?
weak
Spironolactone is used in combination with other diuretics, why?
- never used for substantial diuresis alone
- can help obviate hypokalemia from other diuretics
Explain the anti-mitogenic properties of spironolactone?
- hypertrophy (cardiac and smooth muscle)
- fibrosis (myocardial and vascular)
- aldosterone-escape with ACE
Why is CHF therapy with diuretics alone should be limited to acute, relative short episodes?
- further reduction in CO and azotemia
- AKI risk
- activation of neurohumoral systems and maladaptive responses
How does diuretic therapy induce reduction in CO and pre- or intra-renal azotemia?
overaggressive diuresis without other drugs to improve cardiac performance
How does diuretic therapy induce AKI?
aggressive therapy with ace –> why you should avoid ace
How does diuretic therapy induce neurohumoral systems and maladaptive responses?
chronic administration of even the modest diuretic doses results in activation of these systems
What are the effects of arterial vasodilators?
afterload reduction
What is the effect of venous vasodilators?
preload reduction
What type of vasodilators can be used in heart failure?
- venous
- arterial
- mixed/balanced
What is the MOA of venodilators?
- dilation of capacitance veins (intra-abdominal)
- increased potential vascular volume
- “pulls” blood away from the left atrium/ventricle
- reduces volume of blood in left atrium/ventricle
- reduces filling pressure, relieving extravasation of fluid from vascular space to interstitial space
What drug is a venodilator?
nitroglycerin
What form does nitroglycerin come in?
2% ointment - topical
What is the MOA of nitroglycerin?
- bioconversion within the mitochondria
- aldehyde dehydrogenase –> release of NO
- NO activates smooth muscle soluble guanylyl cyclase (GC) to form cGMP –> inhibits Ca entry into cell –> smooth muscle relaxation
- NO also activates K channels –> hyperpolarization and relaxation
What is the onset of action for nitroglycerin?
rapid –> debate over clinical effect
What are the adverse effects of nitroglycerin?
hypotension with excessive preload reduction
Tolerance to nitroglycerin develops rapidly within days depending on frequency of dosing due to what?
- depletion of sulfhydryl group
- inactive aldehyde dehydrogenase
- production of peroxynitrite –> blocks conversion of GTP-cGMP
What are the effects of arterial vasodilation?
- arterial vasodilation reduces systemic vascular resistance
- reduced cardiac work
- reduced activation of neurohumoral systems
What are the effects of arterial vasodilation reducing systemic vascular resistance?
- easier for left ventricle to empty volume of blood
- increase in forward stroke volume/CO
- smaller end-systolic volume
- lower end-diastolic pressure
What is the goal of arterial vasodilation?
~10-20% reduction in SBP (10-20 mmHg) in CHF
should not use in patients with SBP <90 mmHg
What are the adverse effects of arterial vasodilation
- hypotension (weakness, collapse)
- reflex tachycardia (increase cardiac work)
What drugs are arterial vasodilators?
- sodium nitroprusside
- amlodipine (Novasc)
- ACE inhibitors
- angiotensin receptor blockers (ARB) - Telmisartan
- Hydralazine
- Prosozin
Sodium nitroprusside summary
- organic nitrate
- spontaneous release of NO
- ultra rapid effect: 1-2 min onset, 1-2 min offset
- ideal for acute L-CHF
What are the special handling requirements for sodium nitroprusside?
- protect from sunlight
- diluents
What are the adverse effects of sodium nitroprusside?
- hypotension
- converted to cyanide in RBC’s: metabolized to thiocyanate in liver, excreted by kidneys in 7 days
Amlodipine summary
- Ca L-channel blocker
- dihydropyridine class
- distinctly different than diltiazem
- peripheral arterial vasodilation –> minimal myocardial/EP effects
What is the onset of action of amlodipine?
- within a few hours
- half life is 24-36 hours
- 5-7 days to get maximal effect
What are the adverse effects of amlodipine?
- hypotension
- gingival hyperplasia (dogs)
What does ACE stand for?
angiotensin-converting enzyme
What does ACE do?
conversion of angiotensin 1 to angiotensin 2
What are the effects of angiotensin 2?
- vasoconstriction
- Na retention
- aldosterone release
- mitogenic effects
- activates sympathetic nervous system
What converts angiotensinogen to angiotensin I?
renin
What are ACE inhibitors not particularly effective for?
systemic hypertension –> most commonly hyporeninemic
What allows for continued angiotensin II production with ACE inhibitors?
tissue chymases
How do ace inhibitors prolong survival in dogs and cats with CHF?
neurohumoral modulating agent
Ace inhibitors are prodrugs metabolized and excreted where?
metabolized in liver to active form and excreted by the kidney
What is the problem with ace inhibitors?
lose ability for renal autoregulation
What effects are associated with renal autoregulation?
- reduced glomerular efferent arterial vasoconstriction with reduced renal perfusion
- common clinical scenario during CHF tx
- exacerbated by NSAIDs
- AKI
What drugs are considered ACE inhibitors?
- Enalapril
- Benazepril
- Lisinopril
What is the onset, duration, and distribution of enalapril?
- prodrug
- onset: 2-4 hours
- duration: 12-14 hours
- distribution: all tissues except CNS
How is enalapril excreted?
renal and hepatic
How often should enalapril be administered?
BID
How is enalaprilat excreted?
renal
What is the worry with toxicity and enalapril?
even at clinical doses you can end up with AKI
What is the onset, duration, and distribution of benazepril?
- prodrug
- onset: 2-4 hours
- duration: 12-24 hours
- distribution: all tissues except CNS, placenta
How is benazeprilat excreted?
renal and hepatic excretion
T/F: You must be more cautious with enalapril in kidney failure, not as cautious with benazepril.
True
What is the excretion, onset, and duration of lisinopril?
- not a prodrug
- renal excretion
- onset: 2-4 hour
- duration: 12-24 hour
What is the MOA of angiotensin receptor blockers (ARB)?
- antagonizes angiotensin II binding to angiotensin I receptor
- downstream antagonism from ACE
- not subject to tissue chymase limitations
- preclude some of the ACE issues –> does not induce cough
What are the uses of telmisartan (an ARB)?
- only approved drug in vet med
- only approved for tx of systemic hypertension in cats
- off label use for proteinuria dogs
- off label use for refractory systemic hypertension in dogs
Describe the oral absorption, metabolism, and excretion of telmisartan?
- relatively rapid oral absorption
- highly protein bound
- metabolized and excreted by the liver
What are two other arterial vasodilation drugs that are rarely used?
- hydralazine
- prosozin
What drugs are positive inotropes that are sympathomimetics in the drug class of catecholamines?
- epinephrine
- norepinephrine
- dobutamine
- dopamine
What is the effect of catecholamines on the body?
activation of adrenergic receptors
What are the effects of catecholamines on alpha 1 receptors?
precapillary vasoconstriction in organs
What are the effects of catecholamines on alpha 2 adrenergic receptors?
vasoconstriction
What are the effects of catecholamines on beta 1 adrenergic receptors?
- positive inotrope
- positive chronotrope
- positive lusitrope
- positive dromotrope
What are the catecholamine effects on beta 2 adrenergic receptors?
precapillary vasodilation to skeletal muscle
Why is dobutamine an excellent choice for CHF tx?
- B1: ++++
- B2: ++
- A1: +
Describe the drug form, onset, offset, adverse effects, and tolerance of dobutamine
- only available IV (CRI)
- onset: 2 min (peak at 10 min)
- offset: 1-2 min
- adverse effects: arrhythmias
- develops tolerance within 72 hour
Is dopamine use for CHF tx?
nope
Describe the drug form, onset, offset, and adverse effects of dopamine.
- only available IV (CRI)
- onset: 5 min
- offset: 2-5 min
- adverse effects: tachycardia, arrhythmias
What is the MOA of phosphodiesterase inhibitors and their positive inotrope effect?
- increase cAMP
What do phosphodiesterases do?
- degrade nucleic acids –> reducing cAMP
What drugs are considered phosphodiesterases inhibitors?
amrinone and milrinone
Describe the type of inhibitor and drug form of phosphodiesterase inhibitors (amrinone, milrinone)
- type III PDE inhibitors
- IV administration only
What is the use of phosphodiesterase inhibitors?
short term therapy for severe myocardial failiure
What are the adverse effects of amrinone and milrinone?
- arrhythmias
- hypotension
- thrombocytopenia
How is pimobendan a calcium sensitizer?
- increased Ca effect for given [Ca]
- no Ca loading
- positive inotropic
How is pimobendan a phosphodiesterase III inhibitor?
- positive inotrope
- vasodilation
What is pimobendan labeled for in dogs?
- dilated cardiomyopathy
- mitral valve disease (DMVD)
Describe how pimobendan undergoes hepatic demethylation
- converted to ODMP
- 100x more potent than pimobendan
- predominantly PDEIII inhibition
Which drug lasts longer: pimobendan or ODMP?
ODMP
T/F: pimobendan pharmacodynamics do not persist longer than Cmax.
False - persists longer than Cmax
What are the adverse effects of pimobendan?
- generally considered low frequency
- ventricular arrhythmias
- increases AVN conduction velocity –> consideration for atrial fibrillation
What are digitalis glycosides derived from?
- oleander
- lily of the valley
- milkweed
What are digitalis glycosides used for?
treatment of “dropsy” since the Greeks and Romans
What is the MOA of the positive inotrope digitalis glycosides?
- inhibit Na/K ATPase –> increases [Na]
- induces “reverse mode” of Na/Ca exchanger –> increase [Ca], increase release of Ca from SR, increase Ca interaction with TnC
How do digitalis glycosides increase density of Na/K ATPase in heart failure?
- baroreceptor dysfunction
- contributor to increase SNS tone in heart failure
How do digitalis glycosides act as positive inotropes?
- Ca loading
- “neutral” effect on vascular tone
What are the electrophysiologic effects of digitalis glycosides?
- through vagal effects
- direct effects when toxic
Describe the absorption and excretion for the positive inotrope digoxin
- rapid absorption with high bioavailability
- renal excretion
- establishes steady state within 1 week
Describe the toxicity of digoxin
- relatively narrow therapeutic:toxic ratio
- reduced renal function
- decreased K, decreased Mg, increased Ca
- major interactions with almost 300 medications
What happens in low level digoxin toxicity?
- GI
- arrhythmias
What happens in moderate level digoxin toxicity?
arrhythmias
What happens in high level digoxin toxicity?
- arrhythmias
- neurologic
What are the two types of digoxin toxicity related arrhythmias?
- vagal associated
- direct
What happens in vagal associated digoxin toxicity related arrhythmias?
- sinus bradycardia
- AV block
What happens in direct arrhythmias associated with digoxin toxicity?
- ventricular ectopics/tachycardia –> Ca loading (early after depolarization)
- atrial fibrillation
How do you treat digoxin toxicity?
- remove the drug
- address underlying risk factors
- treat arrhythmias if necessary
