Cardiopulmonary Disease Pharm Flashcards
What drug is used commonly to treat CHF?
Furosemide
Furosemide
Lasix
Loop Diuretic
Impairs Na+/Cl-/K+ cotransport in ascending loop of Henle • Increases excretion of Na+, Cl-, K+, H+, Ca++, Mg++ (Can produce hyponatremic hypochloremic alkalosis)
Oral administration -> diuresis in ~1 hr, peaks in 1-2 hrs, duration ~6 hrs
Oral, injectable preparations
AE of Furosimide?
Adverse Effects: Dehydration, electrolyte disturbance (see above) esp. hyponatremia and hypokalemia. Ototoxicity (esp. at high doses and concurrent use of aminoglycoside antibiotics)
Spironolactone
Aldosterone antagonist (as a diuretic it produces only a mild degree of diuresis)
- Inhibits Na+/K+ exchange, when used together with furosemide (K+ wasting), some of the potassium loss is offset (hence its category name ‘potassium-sparing diuretic’)
- Aldosterone blocking may directly benefit CHF via aldosterone receptor-mediated effects in heart, including cardiac remodeling.
- Slow onset diuresis, peaks in 2-3 days.
AE of Spironolactone?
Adverse Effects: Hyperkalemia, facial dermatitis (cats)
Hydrochlorothiazide
Decreases Na+, Cl- and increases Ca++ absorption in distal convoluted tubule • Increases excretion of Na+, Cl-, K+, Mg++
- Mild to moderate diuresis
- Oral administration -> onset ~1 hr, peaks ~4 hrs, duration 6-12 hrs
AE of Hydrochlorothiazide?
Adverse Effects: Dehydration, electrolyte disturbance (see above) esp. hypokalemia. Can cause hypochloremic alkalosis, hyperuricemia.
ACE Inhibitors
“PRIL” Captopril, Enalapril, Afosiopril
Antihypertensive. Blocks ACE in lungs from converting angiotensin I to angiotensin II (powerful vasoconstrictor). Decreases BP, Decreased Aldosterone secretions, Sodium and fluid loss.
Check BP before giving (hypotension)
*Orthostatic Hypotension
Enalapril
Prodrug, activated in liver.
- Prodrug and active metabolite undergo primarily renal clearance, consider dose modifications in renal failure.
- Oral preparation.
Benazepril
Prodrug, activated in liver.
- Less renal clearance than other ACEI’s, 50% in dog, 15% in cats (preferred ACEI for patients with renal disease).
- Oral preparation
Angiotensin Receptor Blocker (ARBs)
Antagonists at the Angiotensin-II receptor
Telmisartan (ARB names generally end in -sartan). Oral preparation • Approved to treat feline systemic hypertension (more effective than ACEI’s), limited data in dogs
Adverse Effects: GI effects (nausea/vomiting/diarrhea), lethargy, weight loss in cats. Hypotension may require dose reduction.
Positive Inotropes
These drugs increase myocardial contractility and in doing so they increase cardiac output in heart failure.
Pimobendan
Called an ‘inodilator’ because it also causes systemic and pulmonary vasodilation.
- Targets multiple processes in the pathology of heart failure • Positive inotrope by increasing the affinity of contractile regulatory proteins to Ca++. Inotropic effect occurs without increased myocardial oxygen demand.
- May also inhibit elements of the neurohumoral response
- Primarily hepatic clearance, biliary excretion (feces)
- oral
AE of Pimobendan?
Adverse Effects: Rarely arrhythmogenic-use cautiously in animals with history of arrhythmia.
Sympathomimetics
These drugs are not typically used to manage chronic heart disease, and are included here because they may be used in other contexts to manage cardiovascular function (e.g. shock, anaphylaxis, severe hypotension…)
Epinephrine
- Agonist at a-1, a-2, b-1 and b-2 receptors, used in CPR, anaphylaxis
- Vasoconstriction, positive inotropy/chronotropy, bronchodilation
- inj preparations
AE of Epinephrine?
Adverse Effects: Hypertension, arrhythmias
Norepinephrine
Agonist at a-1, a-2. Moderate agonist at b-1. Little/no agonism at b-2
- Used as pressor in hypotension, particularly in patients with no other systemic pathology (e.g. renal failure, CHF)
- Administered as CRI
Dopamine
Dose-dependent receptor agonist
-Administered as CRI
- When given at low doses, primary activity at dopaminergic receptors
Dopaminergic receptors, when stimulated, increase renal and mesenteric perfusion.
- Increasing the dose results in beta-1 stimulation (positive inotropy, chronotropy).
- High doses cause activation of the alpha-1 receptors leading to peripheral vasoconstriction
Dobutamine
Primarily beta-1 agonist, lower level alpha-1 and beta-2 agonism
- Less dramatic changes in blood pressure than dopamine
- Administered as CRI
Vasodilators
Arteriolar dilators relax arteriolar smooth muscle and thereby decrease systemic vascular resistance and left ventricular afterload
Amlodipine (Dihydropyridine CCB category)
CCBs of the dihydropyridine category have their primary effect on vascular smooth muscle (compared to non-dihydropyridine CCBs that have a greater effect in myocardial cells)
- Amlodipine primarily acts on systemic arterioles, reducing LV afterload
- Oral preparation
AE of Amlodipine?
Adverse Effects: Hypotension, bradycardia, gingival hyperplasia (infrequent, in dogs with chronic use, reversible)
Hydralazine
Arterial vasodilator
- Most commonly used in initial management of severe systemic hypertension/hypertensive crisis
- Not preferred for long-term management of heart failure
- Oral, injectable preparation
AE of Hydralazine?
Adverse effects: Hypotension, reflex tachycardia
Nitroprusside
Nitrates
- Not widely used, very $$$. Primarily venous dilation, restricted to IV administration with very close monitoring of blood pressure.
- Injectable preparation
Sildenafil
Phosphodiesterase-V (PDE-V) inhibitor
- -Inhibits PDE-V, which is localized to specific tissues and degrades the vasodilator, cGMP
- Used to treat pulmonary arterial hypertension (also megaesophagus), owing to the tissuerestricted distribution of PDE-V
- Oral preparation
Antiarrhythmics
It is worth noting that most drugs used to manage cardiac arrhythmias can also cause arrhythmias as adverse effects of those drugs. This is not surprising when one considers that these drugs work by modulating electrical impulse formation and conduction in a highly-electrically active organ
- Generally antiarrhythmic drugs work through a relatively small set of electrophysiological changes:
- Slowing tachycardia
- Terminating the re-entry of an aberrant impulse
- Preventing abnormal impulse formation or conduction
Antiarrhythmics Class I
Class I drugs, including lidocaine and mexiletine, block Na+ channels that are key to the rapid action potential upstroke (Phase 0). This slows the speed of the conduction of an electrical impulse. Most drugs in this class lose effectiveness in hypokalemic patients
Lidocaine
Generally the first-choice IV drug for ventricular arrhythmias (bolus, followed by CRI)
- With some exceptions it is generally ineffective in supra-ventricular arrhythmias.
- Ineffective orally, complete clearance by first-pass metabolism
AE of Lidocaine?
Adverse Effects: Arrhythmias, CNS (tremors, seizures) at high doses. Cats more prone to adverse effects.
Mexiletine
Similar MOA to lidocaine
- Orally effective, primarily hepatic clearance
- oral prep
AE of mexiletine?
Adverse Effects: GI, arrhythmias, excitement
Antiarrhythmics Class II
Class II is composed of beta-adrenergic antagonists. Both non-selective (b-1 and b-2 antagonism) and cardioselective (b-1 antagonism) drugs comprise this class. Beta-1 blockade slows heart rate, slows atrioventricular conduction velocity, and increases refractoriness to impulses. Beta blockers are used in both supraventricular and ventricular arrhythmias, particularly those induced by enhanced SNS output. Beta blockers are considered first line drugs for both supraventricular and ventricular arrhythmias in cats.
Atenolol
Selective b-1 blocker
- Commonly used to slow sinus rate and AV conduction, and to suppress sympathetically mediated ventricular premature beats
- Oral preparation
AE of Atenolol?
Adverse Effects (more common in elderly, severe heart disease): Bradycardia, lethargy, inappetence, hypotension. Negative inotropic effects can exacerbate heart failure.
Sotalol
Sotalol has both non-selective beta blocking activity (Class II) as well as potassium-channel inhibiting activity (Class III)
Non-selective beta-blocker, with Class III effects at higher doses.
-Renal clearance
-oral preparation
AE of Sotalol?
Adverse Effects: Negative inotropic effects can exacerbate heart failure, arrhythmias, dyspnea, bronchospasm
Antiarrhythmics Class III
Class III antiarrhythmics block a subset of potassium channels that open in Phase 3 repolarization, prolonging the action potential duration and the effective refractory period (the period in which the cell will not generate a new action potential if stimulated). Conduction velocity is not prolonged by Class III drugs. These drugs are effective treatments for ventricular arrhythmias, particularly those cause by reentry.
Antiarrhythmics Class IV
Class IV antiarrhythmics are calcium-channel blockers (CCB’s). Class IV drugs target calcium channels in vascular tissue, where they regulate vasoconstriction, and in the heart, where they regulate pacemaking and myocardial contractility
Diltiazem
Non-dihydropyridine CCB, targeting both vascular and cardiac tissue.
- Slows AV conduction, potent coronary and mild peripheral vasodilation
- Positive lusiotrope (increases rate of myocardial relaxation), particularly beneficial in restrictive heart disease, e.g. feline HCM
- Comparatively lower negative inotropy than other non-dihydropyridine CCB’s
- Hepatic clearance, chronic dosing prolongs t 1/2
- Oral preparations available as immediate release and extended-release (e.g. Diltiazem ER), also available as injectable
AE of Diltiazem?
- Adverse effects: GI, lethargy, hypotension
Digoxin
Positive inotrope, this indication largely now filled by pimobendan
- Negative chronotrope
- Anti-arrhythmic effect via increasing PNS output to SA, AV nodes, atria
- Narrow therapeutic range -> therapeutic monitoring of plasma levels
- Clearance primarily renal in dogs, combined renal/hepatic in cats
- Digoxin toxicity not uncommon (narrow therapeutic range), long list of factors that predispose to toxicity (e.g., azotemia, hypokalemia drug-drug interactions)
- Oral preparations
AE of Digoxin?
Adverse Effects: GI (vomiting/diarrhea), cardiac (arrhythmias), CNS (depression, disorientation) Treatment symptomatic, correct predisposing factors (e.g., K+), Fab anti-digoxin
Anti-thrombotics
Thrombosis is a well-characterized sequela to cardiovascular pathological processes. Feline hypertrophic cardiomyopathy (HCM) is a prototypical disease process that benefits from anti-thrombotic therapy. Given the role of platelet attachment/aggregation in initiating thrombus formation, it is not surprising that drugs targeting platelet aggregation can be effective anti-thrombotics
Aspirin
- Irreversibly inhibits COX-1 production of thromboxane in platelets (necessary for platelet activation/adhesion/aggregation)
- Inconsistent therapeutic effect at low doses
- oral preparation
AE of Apirin?
-Adverse Effects: Narrow therapeutic range, GI: vomiting, Gastric ulcer disease, Bleeding
Clopidogrel
Antagonist at ADP receptor responsible for signaling platelet activation
- Superior platelet inhibition vs. aspirin
- Prodrug, hepatic metabolic activation, substantial individual variability
AE of Clopidogrel?
bleeding
Melarsomine
Arsenic-based drug that impairs metabolism in adult worms
- Not recommended in feline HWD (often self-limiting, low adult worm load, complications from adulticide). Not recommended for dogs with Class 4 HWD until after surgical removal of adult worms.
- AHS recommends 3-dose treatment for dogs, 1st after 8 weeks of macrocyclic lactone/doxycycline, 2nd and 3rd one month later separated by 24 hrs.
- Deep IM injection into epaxial muscles. Injection site reactions common.
AE of Melarsomine?
Adverse Effects: Narrow therapeutic range: anorexia, injection site reactions, lethargy/ depression, inc. hepatic enzymes
Doxycycline
Tetracycline-class antimicrobial
- In HWD, doxycycline targets Wolbachia, an obligate endosymbiont bacteria essential for D. immitis development, reproduction, and adult survival. Wolbachia likely releases biomolecules that contribute to systemic inflammatory response that is prominent in HWD pathology
- AHS recommends doxycycline treatment for weeks 1-4 following diagnosis (4 weeks prior to adulticide)
- Oral solid and suspension, injectable preparations
AE of Doxycyclin?
Adverse Effects: Renal tox at high doses, esophageal irritation/damage with solid dose formulations, esp. in cats -Recommend “chasing” oral dose with water
Prednisone/Prednisolone
Glucocorticoid anti-inflammatory
- Used to reduce immune response to Wolbachia, adult worms, and microfilariae as well as the immune response to their biomolecule release during treatment.
- In patients with substantial microfilarial loads, treatment with glucocorticoids and antihistamines prior to macrocyclic lactones may reduce immune response/anaphylaxis
- Prednisone is a prodrug requiring hepatic activation. Use prednisolone in patients with hepatic impairment, and in cats and horses (poor absorption and/or bioactivation of prednisone)
- Oral, injectable preparations
AE of Predisone?
Adverse Effects: Polyphagia, PU/PD, GI ulceration, hepatopathy, hyperglycemia, delayed wound healing, immunosuppression. In patients with heart disease, glucocorticoid-induced increased systolic blood pressure can worsen status.
Ivermectin
Avermectin class of macrocyclic lactones
- Lipophilic drug, primarily hepatic-biliary-GI clearance of un-metabolized drug (this explains why dogs eating feces from recently treated horses can ingest toxic levels of ivermectin)
- Excluded from CNS by mdr1 efflux pump. Some dogs carry variant mdr1 genes/proteins and are susceptible to CNS toxicity at high doses (e.g. mitocidal therapy). At microfilaricidal/HWD prophylactic doses these patients are not at elevated risk of toxicity. Review Multidrug Sensitivity in Herding Breeds from the Veterinary Clinical Pharmacology Laboratory at Washington State University
- Oral, injectable, spot-on preparations
AE of Ivermectin?
Adverse Effects: Primarily focused on CNS: salivation, depression, ataxia, visual, coma, death.
-Treatment of toxicity supportive, intravenous lipid emulsion may be beneficial
Milbemycin
Milbemycin class of macrocyclic lactones
- Similar MOA, toxicity as ivermectin, used as microfilaricidal/HWD prophylactic
- Better tolerated at high (e.g. mitocidal) doses than other macrocyclic lactones
- Milbemycin is the most potent microfilaricide of the macrocyclic lactones, may precipitate immune reaction in patients with substantial microfilarial loads.
- Oral preparation
AE of Milbemycin?
Adverse Effects: CNS toxicity risk elevated in dogs with variant mdr1 treated with high doses
Moxidectin
Milbemycin class of macrocyclic lactones
- Similar MOA, toxicity as ivermectin, used as microfilaricidal/HWD prophylactic
- Oral preparations
Antitussives
Coughing can be a beneficial response to some respiratory disorders by moving exudative secretions and foreign material out of the airways. In other contexts, excessive coughing can be non-beneficial, potentially harmful, and become self-perpetuating in that the irritation produced from coughing can further stimulate the cough reflex. In animals susceptible to, or suffering from, tracheal collapse excessive coughing can contribute to the pathology.
Dextromethorphan
Little/no activity at opioid receptors. May have analgesic/behavioral effects by blocking NMDA receptors. Antitussive activity likely due to receptor agonism in cough center (omega-1 receptors) that inhibits neurotransmission
- Effectiveness in dogs is variable, low bioavailability
- Adverse Effects: GI, ataxia
Opioid antitussives
Opioid antitussives acting at the mu receptors reduce responsiveness of the cough center (medulla) to afferent stimuli and may also modulate activity at peripheral afferent sensory neurons.
Hydrocodone
mu-active opioid prodrug with hepatic bioactivation
- oral preparations, standard and extended release
- may be combined with atropine (theoretically could provide decreased respiratory secretions, but typically included at doses that prevent drug abuse/diversion and not at parasympathetic inhibitory doses)
- Adverse Effects: Sedation, constipation, bradycardia, paradoxical excitement in some animals.
- Adverse effects more prominent in cats.
Butorphanol
Primarily agonist at kappa receptor, weak mu antagonist -Antitussive effects more potent than morphine or codeine
- Adverse Effects: mu adverse effects are minimal. Sedation, dysphoria (esp cats), reduced GI motility can occur.
- Oral, injectable preparations
Bronchodilators
Patients with respiratory disease processes that involve reversible constriction of small airways can benefit from drugs that cause smooth muscle relaxation leading to bronchodilation
Adrenergic Agonists
In the context of respiratory disease adrenergic agonists are primarily used for beta-2 agonist activity that provides dilation of the small airways in diseases such as feline asthma, as well as in bronchospasm in inflammatory airway disease.
Terbutaline
b-2 selective agonist
- Adverse Effects: Tachycardia, arrhythmia, muscle tremors (“spillover” to b-1 agonism). Inhibit uterine contraction in pregnancy. Hypokalemia at high doses.
- injectable and oral preparations
Albuterol
b-2 selective agonist
- similar adverse effect profile as terbutaline
- oral, solutions for inhalation, and aerosolized preparations (inhalers)
Methylxanthines
Bronchodilators that function through non-specific phosphodiesterase inhibition, increasing cAMP levels. These drugs possibly also act as adenosine receptor antagonists. They may also have antiinflammatory properties. Primarily used in inflammatory airway disease.
Aminophylline
salt of theophylline, formulated to enhance oral absorption without gastric side-effects. Rapidly converted to theophylline (also available as a therapeutic drug).
- nonselective phosphodiesterase inhibitor, increases cAMP concentration in airway smooth muscle cells leading to bronchodilation
- CNS stimulant (use with caution in patients w epilepsy). Stimulates gastric secretion.
- Adverse effects: GI: nausea, vomiting/diarrhea. Cardio: tachycardia, arrhythmias. CNS effects: excitement, tremors, seizures. -Narrow therapeutic range, therapeutic drug monitoring recommended
Anti-inflammatory Drugs
The anti-inflammatory effects of glucocorticoids provide benefit in the treatment of non-infectious inflammatory airway disease (e.g., canine chronic bronchitis, feline asthma). Systemic therapy (e.g., prednisone/ prednisolone) or local installation (fluticasone proprionate) in metered dose inhalers are treatment options. Local therapy has the advantage of allowing locally high concentrations of drug to the affected respiratory tissue, while offering lower ‘total body’ dose that would reduce the risk of some adverse effects seen at systemic doses.
Atropine
Adverse effects predictable for PNS inhibition: include xerostoma, ileus, constipation, tachycardia, urine retention
- Injectable preparations
Glycopyrrolate
primarily used in anesthesia/surgical procedures • longer duration of effect vs. atropine
- Injectable preparations
- Similar adverse effects as atropine
