Cardio MoA Drugs Flashcards
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:
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.
Dobutamine
what is it:
receptors:
usually used for:
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.
Ephedrine
what is it:
receptors:
usually used for:
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.
Norepinephrine
what is it:
receptors:
usually used for:
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
Phenylephrine
what is it:
receptors:
usually used for:
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?)
Vasopressin
what is it:
receptors:
usually used for:
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
Angiotensin
what is it:
receptors:
usually used for:
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
Epinephrine
what is it:
receptors:
usually used for:
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)
Isoproterenol
what is it:
receptors:
usually used for:
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
Dopexamine
what is it:
receptors:
usually used for:
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.”
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
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
Sildenafil:
MoA:
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)
Pimobendan:
MoA:
PDE3i prevents degradation of PDE3 increasing
Cardiac myocyte - inotrope MoA:
Vascular smooth m. vasodilator MoA:
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
Procainamide MoA: route: dose: cats: Adverse effects:
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
Class Ib Antiarrhythmic Agents
MoA:
Is lidocaine more or less effective in presence of acidosis, > extracellular K, and partially depolarized cells:
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
Lidocaine
max dose:
clearance:
cats/adverse effects/dose:
adverse effects:
How do you treat lidocaine-induced seizures.
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
Mexiletine
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
Class II Antiarrhythmic Agents
MoA:
used for:
contraindicated:
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
Esmolol
route and dose:
adverse effect:
atenolol and metoprolol:
propranolol:
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
Class III Antiarrhythmic Agents
MoA:
risk:
risk is increased with:
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
Sotalol
MoA:
indicated for:
adverse effects:
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
Amiodarone
MoA:
adverse effects:
amiodarone (Cordarone IV) can = severe hypotension effect has been attributed to the vasoactive solvents of the formulation:
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 $
Class IV Antiarrhythmic Agents MoA: drug class: indications: contraindicated in:
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
Diltiazem
dose:
MoA:
adverse effects:
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
