Cardiac Pharmacology Flashcards
List 6 mechanisms by which a heart can fail?
pump/mechanical failure
obstruction to. forward flow via stenosis or hypertension
regurgitant flow via valve dysfunction
congenital shunt causing volume overload in certain chambers
conduction disorders like arrhythmias
reduced fluid return from vessel rupture or vasodilation resulting in reducing preload
What are 6 compensatory mechanisms that occur in response to heart failure?
increase heart rate
increase peripheral resistance
redistribution of blood flow
increase blood volume
myocardial hypertrophy
cardiac dilation
Explain how cardiac function is controlled? How do acute and chronic outcomes compare?
PSNS reduces the heart rate via the vagus nerve
SNS increases heart rate and contractility via sympathetic cardiac nerves
acute increases in sympathetic tone result in
- increased heart rate
- increase cardiac output
- increase TPR
chronic increases in sympathetic tone result in
- persistant tachycardia
- adrenergic receptor downregulation
- increased myocardial oxygen demand
- myocyte necrosis
Define cardiac output
heart rate x stroke volume
What are the physiologic features of skeletal muscle?
they have
- intercalated discs/gap junctions
- branched
- central nucleus
Explain the mechanism of how heart disease causes congestive heart failure?
Heart disease reduces cardiac output
reduced cardiac output results in reduced blood pressure
low blood pressure causes:
- reduced renal perfusion and that stimulates renin production
- sympathetic activation (of alpha and beta receptors)
- Renin = increased angiotensin 2
- stimulates increased aldosterone and ADH (also stimulate SNS activation and vassoconstriction)
- water and Na retention
- increase blood volume
- increase hydrostatic and lower oncotic pressure
- edema and increased preload
- cardiac dilation = further reduces cardiac output - SNS activation results in vasoconstriction and an increase in heart rate and TPR
- vasoconstriction will increase heart rate and TPR
- this increases afterload and cardiac work resulting in reduced cardiac output
Explain the steps of RAAS activation and its impacts on the heart.
- reduced blood pressure stimuli
- juxtaglomerular cells release renin
- renin converts angiotensinogen to angiotensin 1 in liver
- angiotensin 1 to angiotensin 2 converted in the lungs by angiotensin converting enzyme
- ACE interacts with bradykinin causing vasoconstriction
- angiotensin 2 causes vasoconstriction, SNS activation , increased aldosterone release
- aldosterone increases sodium and water retention = increasing blood volume
vasoconstriction will increase afterload
aldosterone will increase preload
What are the gross systemic effects of heart failure?
pulmonary edema from LS heart failure
liver congestion, subcutaneous edema, ascites from RS heart failure
edema is from increased preload
What is the most common kind of heart disease causing heart failure in dogs? How does the prevalence compare to other types of heart disease
myxomatous valvular degeneratioin
small dogs
mitral valve collagen degeneration causes valve regurgitation
- increases cardiac work
- ventricular remodeling and dysfunction
myxomatous > congenital heart disease > DCM > hemorrhagic pericardial effusion > neoplasia > dirofilaria
List the common causes of heart disease/failure in cats
HCM > DCM > hyperthyroid associated hypertrophy > congenital
List 6 factors that cardiac drugs can target
chronotropy
inotropy
peripheral resistance/vascular tone
blood volume (diuresis/fluid)
rate of conduction/rhythm
neurohormonal input
What are 5 potential goals of cardiac drugs
Modify (1+)
preload
afterload
rate/rhythm
contractility
SNS/neurohormonal input
Explain the frank starling law/mechanism is?
It says that by increasing preload it will increase cardiac output up until a certain point
- disease reduces the threshold of preload that will ‘max’ the capacity of cardiac output
(healthy animals are moderate, when exercising the threshold is increased)
How do cardiac drugs affect cardiac output in terms of the frank starling law
diuretics will act to reduce the preload
positive inotropes will increase cardiac output
mixed vasodilators will act to both increase cardiac output and reduce preload
On the frank starling curve, preload is on the x axis and cardiac output is on the y axis.
We are using these drug to optimize cardiac output and reduce increased blood pressure associated with high preload and CHF (>25mmHg)
If CHF is severe and has both forward and backwards failure you may need a diuretic and a positive inotrope
What is a physiologic reflex in response to drug administration? + example
It is an indirect response to a drug
furosemide will reduce blood volume
- renal vasodilation and reduced bp
- RAAS activation
- increasing SNS and heart rate
What are the categories of drugs that can directly target the heart? And the types/classes of drugs under each category
inotropes
- adrenergic
- inodilator
- cardiac glycoside
chronotropes
- adrenergic
- cholinergic
antiarrhythmics
class
1 - Na channel blocker
2 - beta blocker
3 - potassium channel blocker
4 - Ca channel blocker
Explain the process of cardiac muscle contraction
it is similar to skeletal muscle contraction except it is synchronous
- resting membrane potential = -90mV
- because there is more extracellular potassium - Na channel inactive while K and Ca channels are open
- Ca enters and triggers Ca release from sarcoplasmic reticulum
- Ca binds troponin which allows actin and myosin to interact
- not all the troponin will interact with Ca so you can control muscle contraction by controlling the amount of Ca available - Ca is removed by Na/Ca pump exchanger or returned to sarcoplasmic reticulum
- intracellular Na homeostasis returned via Na/K pump
What is the main function of positive and negative inotropes respectively
+ = used to treat reduced cardiac output
- = can be used to reduce myocardial O2 consumption but not used as much
List 3 examples of short term positive inotropes
dobutamine
dopamine
epinephrine
List 2 examples of chronic use positive inotropes
digoxin
pimobendan
What is digoxin? What is its mechanism of action?
it is a cardiac glycoside from the foxglove plant
It inhibits Na/K pump causing an increase in intracellular sodium
- increased intracellular Na = reduced action of Na/Ca exchanger
= more intracellular Ca
What are the effects of digoxin
reduce heart rate
- restore baroreceptor sensitivity = reduced SNS and increase PSNS
increase inotropy
increase cardiac output
What is digoxin used for
atrial fibrillation (by increasing PSNS)
not normally used
its efficacy is not well studied
What are the adverse effects associated with digoxin
arrhythmias (impact K)
electrolyte interactions
drug interactions (careful with furosemide)
GI effects - v and anorexia
It has a long half life
- dog = 24-39h
- cat = 33-58h
What are the effects of pimobendan
positive inotrope
vasodilator
This results in increased contractility without increased myocardial oxygen demand
What is the mechanism of action of pimobendan
Increase inotropy by…
- sensitizes troponin C to Ca
- inhibit phosphodiesterase 3 in heart = increase cAMP
Reduce pre and afterload by…
- inhibiting phosphodiesterase 3 and 4 = cAMP/cGMP accumulation = vein and artery dilation
cAMP is made after norepinephrine binds the beta 1 receptor by adenylyl cyclase
- result in increased cAMP, strength and rate of contraction, rate of AP conduction
In what cases is pimobendan contraindicated
HCM
aortic stenosis
arrhythmia
= situations where increasing cardiac output could be bad
In what cases is pimobendan indicated
DCM
mitral valve insufficiency
What are the pharmacokinetic features of pimobendan
short half life (30min in dogs with 2hrs of active metabolite)
93%/mostly protein bound
excreted in feces
What are the instructions for pimobendan administration
PO 1hr before meal
What are the adverse effects of pimobendan
usually safe/well tolerated
GI effects
tachycardia - at high doses
PU/PD
CNS toxicity
Which 2 positive inotropes are B1 agonists? How are they administered?
dopamine and dobutamine
IV only (low bioavailability)
What is the mechanism of action of dopamine/dobutamine? What class of drug are they?
beta agonists
Heart - act on beta 1 receptors
- norepi + B1 result in increased cAMP
- result in phosphorylation of Ca channel by protein kinase A
- increases Ca entry
- increased Ca release from sarcoplasmic reticulum
Vessels - B2 receptor targets
- B2 activation results in increased cAMP
- increased cAMP inhibits the myosin light chain
- vasodilation
B2 activation will also cause bronchodilation
What is the effect of dobutamine? How is it administered?
positive inotrope + no impact on heart rate (at normal doses)
- no renal vasodilation
CRI (because half life is 2 mins)
What are the adverse effects associated with dobutamine
seizures in cats*
expensive
don’t use with bicarbonate
tachycardia at high doses
mut fix hypovolemia before administration
What cardiac conditions is dobutamine indicated for
cardiogenic or septic shock
short term CHF treatment with pimobendan
What receptors does dopamine activate in the context of cardiac drugs? What are the effects of activation?
It act on many receptors
dopamine 1 receptors
- kidney vasodilation
beta 1 receptor
- increase inotropy
alpha 1 receptor
- increase peripheral vascular resistance
alpha 2 receptors
How is dopamine administered and what are the adverse effects?
CRI because of short half life
adverse
- vasoconstriction of the kidney at high doses
- extravascular administration will cause tissue necrosis
- arrhythmia
What conditions may indicate the use of dopamine?
cardiogenic or septic shock
oliguria
What are the effects of epinephrine administration?
bronchodilation via beta 2 receptors
positive inotrope and chronotrope via beta 1 receptors
increase peripheral resistance
What are the adverse effects of epinephrine administration
arrhythmia
What are the conditions that may indicate epinephrine administration
cardiac arrest
anaphylactic shock
Give 3 examples of negative inotropes
beta antagonists
calcium channel blockers
some antiarrhymatics
What are 2 classes of chronotrope drugs
beta antagonists/blockers
muscarinic antagonists/anticholinergics
List 3 negative chronotropic drugs commonly used
propranolol
atenolol
carvediol
=beta antagonist
List 2 positive chronotropic drugs commonly used
atropine
glycopyrrolate
- anticholinergics
What is the mechanism of action of beta antagonists
They are competitive antagonists of beta receptors
selective or non selective
oppose normal action
beta 1
- increase heart rate, contractility
- increase conduction velocity
beta 2
- smooth muscle relaxation resulting in peripheral vasodilation and bronchodilation
beta antagonsists will oppose the above effects
What is the mechanism of action of propranolol? What are the effects?
It is a beta 1 and 2 antagonist
- reduces chronotropy and inotropy
- vasoconstriction and bronchoconstriction
What is propranolol primarily used for
antiarrhythmic
short term treatment of hypertension secondary to thyrotoxicosis or pheochromocytoma
CHF with tachycardia
slow ventricular filling in atrial fibrillation
to reduce SNS input to the heart
What are the adverse effects associated with propranolol
bradyarrhythmia
hypotension
bronchospasm (can be a problem if there is reduced lung function or pulmonary edema)
reduced inotropy
What is the route of administration of propranolol
PO or IV
large first pass effect so the dose for PO is much higher than for IV
What is the mechanism of action for atenolol? WHat are its effects?
It is a beta 1 selective antagonist
- negative inotropy and chronotropy
What are the indications/situation for use of atenolol
tachyarrhythmia and ventricular hypertrophy
HCM in cats
hypertension secondary to CKD
- amlodipine is the first choice tho
it is a good choice if you have concerns about pulmonary function (vs. propranolol)
What is the mechanism of action of muscarinic antagonists on the heart? What are the effects?
block the effects of Ach on M2 receptors in the cardiovascular system
normal functions (opposed)
- reduce SA node depolarization
- reduce atrial contractility and action potential duration
- reduce AV node conduction velocity
- reduce ventricle contractility
M2 receptors are found mainly in the SA and AV node
- normally when it is bound by Ach it reduces the amount of cAMP which causes reduced chronotropy and dromotropy (action potential conduction)
there are less M2 receptors in the cardiac myoctes (not as important)
What is the mechanism of action of atropine? What are its effects?
It is a non specific muscarinic receptor antagonist - blocks Ach interaction with the receptor during PSNS stimulation
dose dependent effects
- low: impact salivary and sweat glands
- higher: cardiac impacts like positive chronotropy and dromotropy and increased cardiac output
along with non specific signs
What are the adverse effects of atropine
GI impact - can cause colic in horses
anticholinergic toxidrome
- delirium
- ocular signs
- dry mouth and skin
- fever
- constipation
- tachycardia
- urinary retention
- cutaneous vasodilation
When is atropine contraindicated
for patients with glaucoma
What situations may indicate atropine use
acute treatments of
- bradycardia
- preanesthetic to reduce salivation and airway secretions (not used anymore)
- sometimes asystole tx or toxicity tx
What is the mechanism of action of glycopyrrolate? How does it compare to atropine?
It is the same as atropine - non selective muscarinic receptor antagonist
much more polar than atropine
- less CNS penetration and related adverse effects
- does not cross placenta
- lower incidence of tachyarrhythmia
- lower the volume of distribution (less movement out of vessels into tissue)
Explain how a normal cardiac rhythm is created
- dominant pacemaker cells in the SA node regularly/spontaneously depolarize
- cardiac myocyte RMP = -90
- depolarization threshold = -70
- creates long uniform AP with refractory periods - AP transmitted to the AV node
- AP transmitted to bundle of His and purkinji fibres throughout the ventricles
the velocity is determined by the PSNS and SNS inputs
What are the phases of a cardiac myocyte action potential? Compare this to a SA node action potential?
myocyte
- phase 0 = Na influx - fast
- phase 1 = K efflux - fast
- phase 2 = slow Ca channel open
- phase 3 = slow K efflux
- phase 4 = restore RMP with Na/K ATPase
effective refractory phase = from phase 0 - early 4
node
- phase 0 = depolarization via Ca influx
- phase 3 = repolarize via slow K efflux
- phase 4 = slow Na influx/Ca influx
no fast Na channel
no true RMP due to spontaneous depolarization
What can cause arrhythmias
disruption of the pacemaker cells
- ectopic pacemaker
- abnormal impulse conduction or AP generation
How are arrhythmias classified?
ventricular
- ventricular tachycardia or fibrillation
- premature ventricular contractions
atrial
- supraventricular tachycardia or atrial fibrillation
- premature atrial contraction
- AV block
List 3 primary mechanisms that antiarrhythmic drugs use
change automaticity
change conduction velocity
change excitability of cells in effective refractory period
all will change membrane ion conductance
Name 2 antiarrhythmic drugs that do not fall into one of the 4 classes
atropine - for bradycardia
digoxin - for supraventricular arrhythmia (ex. fibrillation)
List 3 commonly used Na channel blockers
lidocaine
quinidine
procainamide
What is the mechanism of action of Na channel blockers? What is its effects?
They bind/block the fast Na channels to prevent depolarization of cardiac myocytes
It will reduce the slope and amplitude of phase 0 AP thus reducing conduction velocity
It can change the AP duration and effective refractory period by affecting K channels
It will reduce automaticity of ectopic pacemakers
Of lidocaine, quinidine, and flecainide; what class of Na channel blockers are they and what are their respective effects?
class 1A = quinidine
- increase ERP
- modeate Na channel blocker
- anticholinergic
class 1B = lidocaine
- reduce ERP
- mild Na channel blocker
class 1C = flecainide
- ERP same
- strong Na channel blocker
What is lidocaine used for?
ventricular tachyarrhythmia in anesthesia
- minimal impact on atria
local anesthetic
How is lidocaine administered?
IV
no PO (high first pass effect)
What are the adverse effects associated with lidocaine
vomiting
seizure
muscle fasciculation
- will stop when lidocaine stopped
What are the effects of quinidine administration?
increase ERP in atrium and ventricle
- allow atrial fibrillation conversion
anticholinergic
increase AV conduction speed which increases the risk for ventricular tachycardia
- can pretreat with digoxin to avoid (slow AV conduction) but be careful because quinidine will increase digoxin plasma concentrations
How is quinidine administered
PO in horses
IM or IV in SA
What is quinidine used for
atrial arrhythmia
What is the mechanism of procainamide
same as quinidine
How is procainamide andministered
PO
IM
IV
dogs are the only species that utilize it as a prodrug = they have special values for monitoring
What is procainamide used for
ventricular arrhythmias
What are beta blockers used for
atrial fibrillation
What is the mechanism of K channel blockers
block K channels
slow down repolarization
What is a common K channel blocker? What is its mechanism of action?
sotalol
it is a K channel blocker and a beta blocker
it has no first pass effect = high bioavailability
What is sotalol used for
ventricular + some supraventricular arrhythmia
What is the mechanism of action of Ca channel blockers? What are the effects?
block L-type (slow) Ca channels in vascular smooth muscle, cardiac myocyes, and cardiac nodal cells
vasodilation
negative inotrope/chronotrope/dromotrope
- must be cautious if using in CHF patient
What are Ca channel blockers used for
atrial fibrillation in dogs
HCM in cats
What is an example of a common Ca channel blocker used? What is its mechanism of action?
diltiazem
It is the main Ca channel blocker used for arrhythmias
It blocks Ca channels mainly in the AV node
What are the effects of diltiazem
it has a minimal impact of inotropy
- if they have myocardial disease it can have an effect
vasodilation
negative chronotrope/dromotrope
What is diltiazem used for
supraventricular tachycardia and atrial fibrillation in dogs
- slow heart rate
HCM in cats
- control their heart rate to allow filling
- peripheral vasodilation to reduce afterload
- reduce inotropy to allow filling and let the heart relax
