Cardio MoA Drugs

Question 1

Dopamine:
What is it:
Activity:
D1:
D2:
Does exogenously dopamine cross BBB:
dose related effects (D, B, a):
dopamine and renal blood flow:
usually used for:

Answer 1

endogenous precursor to norepinephrine and CNS NT

has direct β- and α-agonist activity and also releases NE from the sympathetic nerve endings

D1 postsynaptic receptors - vasodilation
D2 presynaptic receptors - inhibit NE sympathetic nerve endings (which promotes less vasoconstriction)

no

1-3mcg/kg/min: D1&2 vasodilatory
5-10mcg/kg/min: β
>15 mcg/kg/mi: a

Dopamine has been reported to increase renal blood flow at dosages of less than 5 mcg/kg/min and may increase UOP but dopamine therapy does not appear to provide any low-dose renal-protective efficacy

modest vasoconstriction and increase in blood pressure with little change or modest increases in cardiac output.

Question 2

Dobutamine
what is it:
receptors:
usually used for:

Answer 2

Dobutamine is a synthetic analog of dopamine with

strong β1-agonist activity
some effects on β2- and α1-receptors
(without dopaminergic effects)

B1/CO

generally causes modest vasodilation and a marked increase in cardiac output with little change in blood pressure

Although dopamine is primarily used to raise arterial blood pressure in hypotensive patients, dobutamine is primarily used to increase forward flow when baseline blood pressure is acceptable.

Question 3

Ephedrine
what is it:
receptors:
usually used for:

Answer 3

Ephedrine is a sympathomimetic amine (but not, strictly speaking, a catecholamine)

Indirect: acts by increasing release of NE from SNS nerve endings
may also have some direct β-agonist effects

general cardiovascular stimulant and bronchodilator

The administration of ephedrine to anesthetized dogs caused a modest decrease in heart rate and an increase in cardiac output, vascular resistance, and arterial blood pressure

effects of a single dose may last 5 to 15 minutes; it may also be administered as a constant-rate infusion 0.02 to 0.2 mg/kg/min

Prolonged use can deplete NE stores
results in tachyphylaxis

also given orally for urinary incontinence (to increase urethral sphincter tone)
In humans it is used topically as a nasal decongestant.

Question 4

Norepinephrine
what is it:
receptors:
usually used for:

Answer 4

A1 B1
primarily an α-receptor agonist - arteriolar & venous constriction
It also exhibits β1-receptor agonist activity causes vasoconstriction and increases BP, with variable effects on heart rate; cardiac output may increase

different CO are attributed to differences in baseline effective circulating volume and myocardial contractility, & capacitance

Animals with an effective circulating volume but with vasodilation would be expected to experience an increase in cardiac output due to venoconstriction of capacitance vessels.

Hypovolemic animals are already vasoconstricted, and further venoconstriction of resistance vessels associated with the administration of a vasoconstrictor would be expected to lead to a further decrease in venous return and cardiac output.

Norepinephrine is commonly used to raise BP

Question 5

Phenylephrine
what is it:
receptors:
usually used for:

Answer 5

α-receptor agonist without β-agonist activity
a1
causes vasoconstriction and an increase BP
and a decrease in heart rate
CO may decrease or increase

earlier discussion regarding the different consequences of venoconstriction for norepinephrine apply

Phenylephrine is used to raise blood pressure (maybe nose bleeds?)

Question 6

Vasopressin
what is it:
receptors:
usually used for:

Answer 6

noncatecholamine vasoconstrictor

V1 receptor that increases intracellular calcium and vasomotor tone

associated with an increase in systemic vascular resistance, a baroreceptor reflex decrease in heart rate, no change in contractility, and no change or a decrease in cardiac output

Terlipressin is a long-acting synthetic analog of vasopressin and is associated with increased systemic vascular resistance and arterial pressure, and a decreased heart rate and cardiac output in people

Vasopressin may be effective in patients hyporesponsive to catecholamines since it operates via different receptors than do the catecholamines, pH

Question 7

Angiotensin
what is it:
receptors:
usually used for:

Answer 7

Angiotensin II is a hormone derived from angiotensin I by angiotensin-converting enzyme primarily in the lung but also in many other tissues

Angiotensin II causes vasoconstriction and aldosterone release

results in an increase in systemic vascular resistance, little change in heart rate, no change in contractility, and little change or a decrease in cardiac output

Angiotensin may be a less potent venoconstrictor than vasopressin, which tends to preserve venous return and cardiac output better than vasopressin

Question 8

Epinephrine
what is it:
receptors:
usually used for:

Answer 8

potent β1-, β2-, α1-, and α2-receptor agonist
potent inotrope and chronotrope, arteriolar and venular vasoconstrictor, and bronchodilator

It potently increases arterial blood pressure and can cause ventricular ectopic pacemaker activity.

Epinephrine is used primarily in supraphysiologic doses (5 to 20 mcg/kg) in emergency situations such as anaphylaxis and cardiac arrest in which the sum of its effects are highly important

Epinephrine can be used to support cardiovascular dysfunction in critically ill patients, but its therapeutic margin may not be as liberal as that of the other catecholamines (higher incidence of sinus tachycardia, ventricular arrhythmias, and increased lactate level)

Question 9

Isoproterenol
what is it:
receptors:
usually used for:

Answer 9

potent β-receptor agonist with no α-receptor activity

potent vasodilator and hypotensive agent

isoproterenol increases heart rate and cardiac output, and decreases blood pressure

if isoproterenol is administered very carefully while blood pressure is monitored and maintained, it can provide potent augmentation of forward blood flow and tissue perfusion

Question 10

Dopexamine
what is it:
receptors:
usually used for:

Answer 10

Dopexamine is a synthetic analog of dopamine(like dobutamine) that is a potent β2 and D1 (unlike dobutamine) receptor agonist without substantial β1 or α1 activity

B2, D1

primarily an arteriolar vasodilator without substantial venous effects and without substantial chronotropic

usually associated with decrease in SVR

Dopexamine is not commonly used in veterinary medicine. It is used in humans for short-term support in congestive heart failure, in which the major benefit is attributed to afterload reduction.

Although dopexamine is a catecholamine, it might more appropriately be listed under the heading “vasodilator.”

Question 11

Class I Antiarrhythmic Agents
MoA Class I agents:
relative potency of their sodium channel effects:
effects on other channels:

MoA Class Ia Antiarrhythmic Agents:

moderate blockade of rapid component of:

prototypical agent

Answer 11

inhibit fast Na channel
decreasing the slope of phase 0 of AP

whether block activated or inactivated Na channel
determine their subclassification.

Class Ia agents have powerful, fast Na channel–blocking

delayed rectifier potassium current (IKr)

IKr blockade results in action potential prolongation and can account for the proarrhythmic effects associated with these drugs in some genetically predisposed individuals

Procainamide is the prototypical agent
quinidine, procainamide, and disopyramide

Question 12

Sildenafil:
MoA:

Answer 12

PDE5i protects cGMP degradation by cGMP-specific PDE5

Nitric oxide (NO) binds to guanylate cyclase receptors, increased levels of cGMP, leading to smooth muscle relaxation (vasodilation)

Question 13

Pimobendan:
MoA:
PDE3i prevents degradation of PDE3 increasing

Cardiac myocyte - inotrope MoA:

Vascular smooth m. vasodilator MoA:

Answer 13

PDE3i prevents degradation of PDE3 increasing
cAMP (similar to B2 stimulation)

Cardiac myocyte:
= increased cAMP = increased PKA
(RyR > release Ca++, phosphorylates phospholamban = > SR SERCA uptake, enhances Ca++ binding to TN-C)

Vascular smooth m.:
= increased cAMP = decreased MLCK (myosin light chain kinase) = smooth muscle relaxation

Question 14

Procainamide 
MoA: 
route:
dose:
cats:
Adverse effects:

Answer 14

Procainamide class 1a
fast Na and delayed Ikr (K rectifying current)

depresses conduction velocity and prolongs ERP
in atrial and ventricular myocardium, accessory atrioventricular (AV) pathways, and retrograde fast AV nodal pathways

parenterally for acute VT, SVT
slowly to prevent hypotension

procainamide is more effective than lidocaine for acutely terminating ventricular tachyarrhythmias in human patients

doses of 6 to 8 mg/kg IV over 5 to 10 minutes
CRI of 20 to 40 mcg/kg/min

cats parenteral procainamide is used cautiously

sustained-release oral procainamide is not commercially available anymore; however, certain compounding pharmacies offer 10 to 30 mg/kg orally (PO) q8h

GI anorexia, nausea, and vomiting
systemic lupus erythematosus is ID rarely in vet. med.
(reported in 1/3 of humans)

A four-way trial of antiarrhythmic drugs in Boxer dogs with ventricular tachyarrhythmias showed that sustained-release procainamide administered at 20 to 26 mg/kg PO q8h reduced the frequency of ventricular ectopy but did not alter the frequency of syncope

Question 15

Class Ib Antiarrhythmic Agents
MoA:

Is lidocaine more or less effective in presence of acidosis, > extracellular K, and partially depolarized cells:

Answer 15

inhibit the fast Na channel
primarily in the open state w rapid onset-offset kinetics

window sodium current is also inhibited, which results in the shortening of action potential duration in normal myocardial tissue. This window current is considered to be the steady-state component of the fast sodium current (INa) resulting from the crossover of the activation and inactivation curves, which govern the opening of the sodium channel.

rapid kinetics explain why class Ib agents have minimal effects on the shorter atrial action potential

Na channel blockade enhanced
Thus these drugs selectively suppress automaticity and slow conduction velocity in ischemic and diseased ventricular myocardium

Question 16

Lidocaine
max dose:
clearance:
cats/adverse effects/dose:

adverse effects:

How do you treat lidocaine-induced seizures.

Answer 16

benefit of minimal hemodynamic, sinoatrial, and AV nodal effects at standard dosages

bolus can be repeated to a max 8 mg/kg w.in 10-minute
CRI of 25 to 75 mcg/kg/min

Hepatic clearance determines its serum concentration directly related to hepatic blood flow
.:. heart failure, hypotension, and severe hepatic disease .:. predispose the patient to lidocaine toxicity

cats adverse effects is much higher - reports of bradyarrhythmias and sudden death
doses of 0.25 to 0.75 mg/kg slow IV
CRI 10 to 20 mcg/kg/min

GI: nausea, vomiting, lethargy
Neuro: tremors, and seizure
resolve quickly with cessation of the infusion

Diazepam

Question 17

Mexiletine

Answer 17

oral class Ib 
highly protein bound and eliminated by renal excretion

adverse effect profile mirror those of lidocaine

ventricular tachyarrhythmias are acutely responsive to lidocaine and can be combined with class Ia, II, or III agents. Typical dosing in dogs is 4 to 8 mg/kg PO q8h

Question 18

Class II Antiarrhythmic Agents
MoA:
used for:
contraindicated:

Answer 18

β-Adrenergic antagonists, or β-blockers
class II agents
(1) inhibit the current If “funny” nodal pacemaker current that also promotes proarrhythmic depolarization in damaged cardiomyocytes
(2) inhibit the inward calcium current, ICa-L, indirectly by decreasing tissue cAMP

B1 - Gs - cAMP - PKA phosphorylate L-type channels

effect increased in higher adrenergic states

slow AV nodal SVT, SA SVT, inappropriate sinus tachycardia (pheochromocytomas), and suppress VT thought to be caused by increased sympathetic tone

inferior to that of the calcium channel blockers

first-line antiarrhythmic agents in cats with VT or SVT

β-Blockers are contraindicated in patients that have evidence of sinus nodal dysfunction (sinus arrest, sinoatrial block, persistent sinus bradycardia), AV nodal conduction disturbances, pulmonary disease (particularly true for nonspecific β-blockers or high-dose β1-selective blockers), or overt congestive heart failure

Question 19

Esmolol
route and dose:
adverse effect:

atenolol and metoprolol:

propranolol:

Answer 19

IV 0.5mg/kg - CRI 50-200mcg/kg/min
short half-life
less effective than diltiazem 
severe drop in LV contractility 
careful monitoring of blood pressure 

most commonly oral β-blockers
relative β1 selectivity and long half-life compared with those of propranolol

Atenolol is water soluble and eliminated by the kidney, whereas metoprolol undergoes hepatic metabolism and elimination. These pharmacokinetic differences should be remembered in choosing a β-blocker and dosage for a particular patient

oral non-selective B blocker with shorter T1/2

Question 20

Class III Antiarrhythmic Agents
MoA:
risk:
risk is increased with:

Answer 20

block the repolarizing IK, which results in prolongation of action potential duration and ERP
phase3

most class III agents block the rapid component of IK (IKr) rather than the slow component (IKs); thus their effects are accentuated at slower heart rates. This puts the patient at risk of early afterdepolarization and accounts for the proarrhythmic effect of class III antiarrhythmic drugs.

concurrent hypokalemia, bradycardia, intact status in females, increasing age, macrolide antibiotic therapy, and a number of other drugs. Amiodarone, with its blockade of both IKs and IKr, makes the action potential pattern more uniform throughout the myocardium and has the least reported proarrhythmic activity of any of the class III agents

Question 21

Sotalol
MoA:
indicated for:
adverse effects:

Answer 21

nonselective β-blockade (phase 0)
IKr inhibition (phase 3)

SVT and VT
class II effects predominate at lower dosages:
sinus and AV nodal depression
class III effects seen at higher dosages:
prolongation AP, ERP

prolongation AP can result in enhanced calcium entry during the action potential plateau and may explain why the negative inotropic effect of sotalol is far less than expected

same absolute and relative contraindications apply to sotalol as to β-blockers in general

1 to 3 mg/kg PO q12h in dogs and cats

most class III agents block the rapid component of IK (IKr) rather than the slow component (IKs); thus their effects are accentuated at slower heart rates. This puts the patient at risk of early afterdepolarization and accounts for the proarrhythmic effect

Question 22

Amiodarone
MoA:

adverse effects:

amiodarone (Cordarone IV) can = severe hypotension effect has been attributed to the vasoactive solvents of the formulation:

Answer 22

broadest spectrum
nonselective β-blockade (phase 0)
IKr inhibition (phase 3)
fast Na (phase 0)
Ca block (phase 0)
properties of all four antiarrhythmic classes

efficacy of amiodarone exceeds other antiarrhythmic compounds, including sotalol, in human patients

incidence of torsades de pointes lower

VT or SVT

major drawback is associated w. a host of multisystemic, potentially serious adverse effects that do not occur with sotalol

retrospective evaluation of the use of amiodarone in Doberman Pinschers adverse effects in 30% of the 20 patients
GI: vomiting, anorexia
hepatopathies
thrombocytopenia

typically is reserved for life-threatening VT or SVT
not responding to other therapy
loading 15 mg/kg PO q24h for 7 to 10 days
then 10 mg/kg PO q24h for 7 to 10 days
5 to 8 mg/kg PO q24h long term

Amiodarone has not been used in cats

polysorbate 80 and benzyl alcohol, both known to exhibit negative inotropic and hypotensive effect

Amio-Aqueous does not contain vasoactive excipients and has been shown to be less toxic but more $

Question 23

Class IV Antiarrhythmic Agents
MoA:
drug class:
indications: 
contraindicated in:

Answer 23

channel–blocking drugs
nondihydropyridine CCB slow AV nodal conduction and prolong ERP

atrial tachyarrhythmias
they can prolong the AV nodal effective refractory period terminating AV node–dependent tachyarrhythmia

generally contraindicated in wide-complex tachyarrhythmias

Question 24

Diltiazem
dose:
MoA:
adverse effects:

Answer 24

gained preference over verapamil because of its more favorable hemodynamic profile (i.e., minimal negative inotropic effect)

0.125 to 0.35 mg/kg slowly IV over 2 min has been used in dogs to immediately terminate a severe AV nodal–dependent tachyarrhythmia or slow the ventricular response rate to an atrial tachyarrhythmia

oral diltiazem q8, which can be difficult

block L-type Ca++ channels (phase 0 - nodal cells)

IV diltiazem, esmolol, and adenosine in healthy dogs demonstrated the superior efficacy of diltiazem in slowing AV nodal conduction while maintaining a favorable hemodynamic profile

hypotension and bradyarrhythmias

Question 25

Digoxin
MoA:
indications: 
dose:
Digoxin has a low therapeutic index; owners must be educated about the signs of toxicity:

Answer 25

indirectly through the autonomic nervous system by enhancing central and peripheral vagal tone
slowing of the sinus nodal discharge rate

also blocks Na/K ATPase, increasing Na intracellular, increaing activity of Na/Ca exchanger - increasing Ca intracellular and increasing inotropy

used orally as an antiarrhythmic agent to slow AV nodal conduction in dogs, particularly those with impaired left ventricular systolic function

0.005 to 0.01 mg/kg PO q12h in a normokalemic dog with normal renal function and 0.0312 mg PO q24-48h in a normokalemic cat with normal renal function

Renal dysfunction
hypokalemia
advancing age, chronic lung disease, and hypothyroidism all predispose to digoxin toxicity

serum digoxin concentrations should be monitored
ideal blood levels remain unknown

Question 26

Magnesium Sulfate
MoA:
indication:
Adverse effects

Answer 26

first-line tx torsades de pointes
variable success to treat drug-refractory VT
arrhythmias in patients with known hypomagnesemia

slowly IV at 30 mg/kg (equivalent to 0.243 mEq/kg) over 5 to 10 minutes

Adverse effects include central nervous system depression, weakness, bradycardia, hypotension, hypocalcemia, and QT prolongation.

Question 27

Adenosine

Answer 27

human ER to terminate AV node–dependent tachyarrhythmias

A study performed by the author showed that adenosine, even at doses of 2 mg/kg, was ineffective in slowing canine AV nodal conduction

Question 28

Do antiarrhythmic agents prevent sudden death:

two reasons to treat arrhythmias: (1) to alleviate significant clinical signs such as weakness, syncope, or precipitation or exacerbation of congestive heart failure by an arrhythmia, and (2) to prolong survival…

Answer 28

no - antiarrhythmic agents can be useful in limiting CS related to tachyarrhythmias and thus potentially can prevent euthanasia of veterinary patients

Antiarrhythmic drugs, in general, have not been shown to do the latter, although they may in veterinary patients by controlling clinical signs and avoiding an owner decision for euthanasia.