CHAPTER 9. Pharmacology
Lauren A. Trepanier, Katrina R. Viviano and Sidonie N. Lavergne
CARDIOVASCULAR DRUGS
I. Diuretics
A. Furosemide
1. Mechanism of action
a. Blocks reabsorption of chloride in the loop of Henle
b. Increases urinary excretion of sodium, chloride, calcium, magnesium, and potassium
c. Mild venodilator, shifting fluid from pulmonary to systemic circulation
2. Indications
a. Congestive heart failure (CHF)
b. Pulmonary edema, pleural effusion, ascites
c. Oliguric renal failure (increases urine flow)
d. Hypercalcemia
3. Side effects: Dehydration, prerenal azotemia, hypokalemia, hypochloremic metabolic acidosis; cats more sensitive to adverse effects
B. Spironolactone
1. Mechanism of action: Aldosterone antagonist
a. Moderate diuretic effect
b. Acts in distal renal tubule and collecting ducts
c. Leads to sodium reabsorption, and potassium and hydrogen secretion
2. Indications
a. Second-line diuretic for CHF
b. Ascites due to portal hypertension. Can be used in combination with hydrochlorthiazide
3. Side effects: Hyperkalemia and gastrointestinal (GI) upset (uncommon)
C. Thiazide diuretics (e.g., hydrochlorthiazide)
1. Mechanism of action
a. Weak diuretic
b. Blocks sodium and chloride reabsorption in the distal tubule
c. Increases calcium reabsorption
d. Decreases potassium and magnesium absorption
2. Indications: Management of ascites and edema; used in combination with spironolactone
3. Side effects: Mild hypokalemia, hypomagnesemia, hypochloremic metabolic alkalosis, hyponatremia; contraindicated with hypercalcemia
II. Vasodilators
A. Angiotensin-converting enzyme (ACE) inhibitors (e.g., enalapril, benazepril).
1. Metabolized by liver to active drugs (enalaprilat or benazeprilat). Enalaprilat excreted in urine; benazeprilat excreted in urine and bile
2. Mechanism of action
a. Blocks ACE (lungs and vascular endothelium). Prevents the conversion of angiotensin I to angiotensin II
b. An arterial and venous dilator
(1) Decreases total peripheral and pulmonary vascular resistance
(2) Decreases systemic blood pressure
3. Indications
a. CHF
(1) Afterload reduction
(2) Shifts blood from pulmonary to venous circulation
b. Hypertension
c. Protein-losing nephropathy
(1) Decreases glomerular protein loss
(2) May decrease mesangial cell proliferation and glomerular fibrosis
4. Side effects and contraindications: GI upset, hypotension, prerenal azotemia, hyperkalemia (uncommon); contraindicated in dehydration
B. Amlodipine
1. Calcium channel blocker that is used as a vasodilator, not an antiarrhythmic
2. Mechanism of action
a. Greatest effect on vascular smooth muscle. Peripheral arteriolar vasodilator
b. Little effect on automaticity, conduction velocity of the atrioventricular (AV) or sinoatrial (SA) nodes, or myocardial contractility
3. Indications: Hypertension
4. Side effects: Negative inotropic effects, hypotension (reflex tachycardia)
C. Nitroglycerin
1. Mechanism of action
a. Venodilator
b. Donor of nitric oxide
c. Reduces preload via pulmonary vein dilation. Shifts blood from pulmonary to venous system.
2. Indications: CHF. Topical use (ointment or patch)
3. Side effects: Hypotension, irritation at site of application, tolerance with continued therapy
D. Hydralazine
1. Mechanism of action
b. Direct action on vascular smooth muscle to decrease contractility by modification of calcium metabolism
c. Decreases systemic vascular resistance
d. Decreases afterload
2. Indications: CHF, severe or refractory hypertension
3. Side effects: Hypotension, reflex tachycardia, GI upset
E. Prazosin
1. Mechanism of action
a. α-1 adrenergic antagonist
b. Balanced vasodilator
c. Reduces preload and afterload
2. Indications: CHF, refractory hypertension
3. Side effects: GI upset, syncope (first-dose effect), development of drug tolerance
III. Antiarrhythmics
A. Class I (e.g., lidocaine, quinidine, procainamide, mexiletine)
1. Shared mechanisms of action
a. Membrane stabilizers
b. Inhibit fast sodium channels
c. Inhibit the rate of spontaneous depolarization
2. Lidocaine
a. Little or no effect on SA or AV nodes or atrial muscle
b. Indications: Drug of choice to treat life-threatening ventricular arrhythmias Not effective orally owing to significant first-pass hepatic metabolism, intravenous (IV) administration only
c. Side effects: Vomiting, central nervous system (CNS) signs (ataxia, depression, nystagmus, seizures; treat with diazepam). Use with caution in patients with hepatic failure; cats more sensitive to CNS side effects (lower doses used)
3. Procainamide
a. Additional mechanisms
(1) Prolongs refractory period in both the atria and ventricles
(2) Decreases myocardial excitability
(3) Anticholinergic effects
b. Indications: Used IV for lidocaine-refractory ventricular arrhythmias
c. Side effects and contraindications: GI upset, do not use with second- or third- degree AV block, drug-induced arrhythmias, may cause hypotension with rapid IV administration; contraindicated in myasthenia gravis
4. Mexiletine
a. Oral analogue of lidocaine
b. Indications: Oral drug of choice for ventricular arrhythmias in dogs
c. Side effects and contraindications: GI upset. Do not use with second- or third- degree AV block
5. Quinidine
a. Prolongs the duration of the action potential and refractory period in both the atria and ventricle. Like procainamide, also has anticholinergic effects
b. Indications
(1) Atrial fibrillation
(a) Direct effect on atrial muscle
(b) Anticholinergic effect prolongs atrial refractory period
(c) Converts atrial fibrillation to normal sinus rhythm in horses
(2) Refractory supraventricular tachycardias
(3) Ventricular arrhythmias
c. Side effects: GI upset, hypotension, worsening of CHF, AV block
d. Contraindications: Digoxin toxicity, myasthenia gravis
B. β blockers (Class II antiarrhythmics)
1. Mechanisms: Adrenergic receptor antagonists
a. Decrease sinus heart rate
b. Increase the refractory period of the AV node
c. Decrease myocardial oxygen demand
d. Decrease cardiac inotropy
2. Propranolol
a. Mechanism: Nonselective β-adrenergic antagonist; both β-1 and β-2 receptor blockade
b. Indications
(1) Supraventricular arrhythmias
(2) Ventricular arrhythmias
(3) Hypertrophic and thyrotoxic heart disease
c. Side effects: Negative inotropic effect, bradycardia, hypotension, decreased hepatic blood flow (decreases clearance of lidocaine), β-2 blockade (hypoglycemia, hepatic receptors; bronchoconstriction, bronchial receptors)
d. Contraindications: Overt heart failure, sinus bradycardia, asthma
3. Atenolol, metoprolol, esmolol
a. Mechanism of action
(1) β-1 adrenergic selective receptor antagonists
(2) Decrease risk of bronchospasm
b. Indications
(1) Supraventricular arrhythmias
(2) Atenolol drug of choice for feline arrhythmias
(3) Hypertrophic and thyrotoxic heart disease
(4) Esmolol used IV only (short half life)
c. Side effects: Negative inotropic effect, hypotension, lethargy, diarrhea
d. Contraindications. Bradyarrhythmias
C. Class III antiarrhythmics
1. Mechanisms: Block potassium channels
a. Prolong the refractory period
b. Increase the duration of the action potential
c. Greatest effects in Purkinje fibers and ventricular muscle
2. Sotalol
a. Combination class II and class III antiarrhythmic
b. Indications: Refractory ventricular arrhythmias; boxer arrhythmias
c. Side effects: Drug-drug interactions, negative inotropy, proarrhythmic, bronchospasm, GI upset
d. Contraindications: Asthma, sinus bradycardia, second- or third-degree heart block
3. Amiodarone
a. Mechanism of action
(1) Structural analogue of thyroid hormone
(2) Inhibits α and β receptors (nonselective, noncompetitive)
(3) Inhibits sodium and calcium channels
(4) Prolongs action potential duration and refractory period
b. Indications. Reserved for refractory ventricular tachycardia
c. Side effects: Many drug interactions, GI upset, neutropenia, hepatotoxicity
d. Contraindications: Second- and third-degree AV block, bradyarrhythmias
D. Calcium channel blockers (class IV antiarrhythmics)
1. Mechanism
a. Block influx of calcium through slow calcium channels during plateau of action potential
b. Slow SA and AV node conduction
c. Decrease vascular smooth-muscle contractility. Systemic and coronary vasodilation
d. Decrease myocardial contractility (negative inotropy)
2. Diltiazem
a. Slows AV conduction velocity and prolongs refractory period (rarely affects SA node conduction)
b. Minimal effect on cardiac contractility
c. Mild peripheral vasodilation
d. Indications
(1) Supraventricular tachyarrhythmias (atrial fibrillation)
(2) Hypertrophic cardiomyopathy (cats)
e. Side effects: Bradycardia (dogs), GI upset (cats), hypotension, arrhythmias
f. Contraindications: Potentiate the negative inotropic and chronotropic effects of β-adrenergic antagonists; severe hypotension, sick sinus syndrome, second- or third-degree AV block
3. Verapamil
a. Pronounced effect on AV node
(1) Increased refractory period
(2) Decreased automaticity and AV conduction
b. Clinically significant negative inotropy
c. Decreased peripheral vascular resistance
d. Indications: Supraventricular tachyarrhythmias
e. Side effects: Increased blood levels of digoxin and theophylline; hypotension (resulting from systemic vasodilation); heart block
f. Contraindications: Use with β-adrenergic antagonists, hypotension, sick sinus syndrome, second- or third-degree heart block
IV. Adrenergic agonists
A. Dobutamine
1. Mechanism of action
a. Synthetic catecholamine
b. Direct β-1 agonist with mild β-2 and α-1 adrenergic effects
(1) Increased myocardial contractility and output
(2) Minimal effects on systemic blood pressure or heart rate
2. Indications: Cardiogenic shock; intended for short-term use (48 to 72 hours)
3. Side effects: β-1 receptor desensitization occurs with prolonged use, ectopic beats, increased heart rate or blood pressure
B. Dopamine
1. Mechanism of action
a. Endogenous catecholamine that acts on α- and β-adrenergic receptors and dopamine receptors
b. Positive inotrope; stimulation of cardiac β-1 receptors
c. Pharmacological effects are dose dependent
(1) Low dose (2 μg/kg/min): Stimulates dopaminergic receptors to increase mesenteric, coronary, and renal blood flow
(2) Moderate dose (5 μg/kg/min): Cardiac β-1 adrenergic stimulation, producing increased cardiac output with minimal effects of peripheral vasculature
(3) High dose (>10 μg/kg/min); Stimulates α-adrenergic receptors producing peripheral vasoconstriction and increased blood pressure
2. Indications: Refractory hypotension; acute renal failure
3. Side effects: Tachycardia, arrhythmias, increased myocardial oxygen demand
4. Contraindications: Pheochromocytoma, ventricular fibrillation, uncorrected tachyarrhythmia
V. Digoxin
A. Mechanism of action
1. Mild positive inotrope. Inhibits Na/K/ATPase pump, promoting Na/Ca exchange and increasing intracellular calcium concentrations
2. Slows rapid ventricular rates; increases parasympathetic tone
3. Neurohormonal modulation. Reduces plasma levels of norepinephrine, aldosterone, renin
B. Indications
1. CHF (decreased contractility): Dilated cardiomyopathy or valvular disease
2. Supraventricular tachycardia (atrial fibrillation)
C. Side effects
1. Digoxin toxicity (narrow therapeutic range). Therapeutic drug monitoring recommended
3. Cardiac: Partial or complete heart block, ventricular arrhythmias
4. Many drug interactions
VI. Phosphodiesterase inhibitors
A. Mechanisms
1. Positive inotropes or vasodilators
2. Inhibit phosphodiesterase type III (cardiac-specific phosphodiesterase)
a. Increased intracellular cAMP
b. Increased myocardial contractility
3. Arteriodilation and venodilation (both pulmonary and systemic vasculature)
4. Potentiate adrenergic signal transduction
a. Increases myocardial contractility (positive inotrope)
b. Increases myocardial relaxation
5. Enhanced cardiac contractility without increased myocardial oxygen consumption
B. Pimobendan.
1. Additional mechanisms
a. Potentiates adrenergic signal transduction (positive inotrope; increases myocardial relaxation)
b. Enhanced cardiac contractility without increased myocardial oxygen consumption
2. Indications: CHF, dilated cardiomyopathy or valvular disease
3. Side effects: Arrhythmias, mild GI upset
C. Amrinone, milrinone
1. Indications
a. CHF (decreased contractility). Dilated cardiomyopathy or valvular disease
b. Arterial hypertension
c. Milrinone is 10 to 20 times more potent
2. Side effects: Arrhythmias, GI upset, thrombocytopenia, hepatotoxicity, fever
PULMONARY DRUGS
I. Methylxanthines (e.g., theophylline, aminophylline [theophylline ethylenediamine salt; 80% theophylline])
A. Mechanisms of action
1. Direct smooth muscle relaxation of bronchi and pulmonary vasculature (bronchodilation and vasodilation)
2. Competitive inhibition of phosphodiesterase: Increases cAMP levels, which increase endogenous epinephrine
3. Competitive antagonism of adenosine
4. Interference with calcium mobilization
5. Other effects
a. Inhibit histamine release (inhibition of mast cell degranulation) and inflammatory mediator release
b. Increase mucociliary clearance
c. Prevent microvascular leakage
d. Increase strength of respiratory muscles
B. Indications: Bronchospasm. Extended released formulations available
C. Side effects: CNS signs (excitement, seizures, restlessness), GI upset, polyuria, polydipsia. Narrow therapeutic range
D. Contraindications: Cardiac arrhythmias, hypertension, gastric ulcers, renal or hepatic disease, hyperthyroidism
II. β-2 adrenergic agonists
A. Mechanisms
1. Relaxation of bronchial smooth muscle
a. Activation of β-2 adrenergic receptors
b. Increased cAMP via activation of adenyl cyclase
(1) Activation of protein kinase A (bronchodilation)
(2) Inhibition of inflammatory cell mediator release
2. Stimulate secretion of mucus
3. Enhance mucociliary clearance
B. Terbutaline, albuterol
1. Selective β-2 adrenergic receptor agonists
2. Indications: Bronchospasm. Albuterol available as inhaler
3. Side effects: Tremors, tachycardia, CNS excitement (secondary to nonspecific β-1 receptor activation at high doses)
4. Contraindications: Cardiac arrhythmias, hypertension, seizures, hyperthyroidism. Use with caution
C. Epinephrine
1. Nonselective β- adrenergic agonists. Stimulates β-1, β-2, and α-adrenergic receptors
2. Indications
a. Allergic reactions (insect bites, urticaria)
b. Acute severe bronchospasm
3. Side effects: Tachycardia, vasoconstriction, hypertension (result of β-1 and β- adrenergic receptor activation)
III. Opioid cough suppressants
A. Butorphanol
1. Mechanism of action
a. Synthetic opioid
b. Mixed agonist-antagonist: κ-receptor agonist, weak μ-receptor antagonist
c. Suppresses afferent input into coughing center (medulla)
2. Indications: Antitussive in dogs with minimal to no sedation; mild analgesia
3. Side effects: Sedation (higher doses); significant hepatic first-pass effect (requires higher oral dosing). Minimal cardiac and respiratory depression
B. Hydrocodone
1. Mechanism of action
a. Opioid agonist
b. Suppression of afferent input into coughing center (medulla)
c. Drying effect on respiratory mucosa
2. Indications: Antitussive in dogs
3. Side effects: Sedation, respiratory and cardiac depression, constipation
IV. Inhaled glucocorticoids: Fluticasone
A. Mechanism of action
1. Trifluorinated glucocorticoid
3. High topical potency
4. Low systemic bioavailability
5. Bronchodilation
B. Indications: Allergic airway disease and feline asthma
C. Side effects: Suppression of hypothalamic-pituitary-adrenal (HPA) axis; contraindicated with acute bronchospasm
GASTROINTESTINAL (GI) DRUGS
I. Histamine type 2 (H 2) blockers (e.g, cimetidine, ranitidine, famotidine)
A. Mechanism: Inhibit H 2 receptors in gastric parietal cells, blocking HCl secretion. Ranitidine may also have some prokinetic activity
B. Indications: Reflux esophagitis, gastric ulcers, mast cell tumors, vomiting from liver or renal disease
C. Side effects and contraindications: Cimetidine is a P450 inhibitor and decreases clearance of many drugs, leading to drug interactions
II. Pump blockers (e.g., omeprazole)
A. Mechanisms: Proton pump inhibitor; inhibits NH+/K+ ATPase and inhibits HCl secretion in gastric parietal cells
B. Indications: Reflux esophagitis, severe gastric ulcers, mast cell tumors, gastrinoma
C. Side effects and contraindications: Omeprazole is a P450 inhibitor and decreases the clearance of some drugs in people
III. Gastroprotectants (e.g., sucralfate, misoprostol)
A. Mechanisms
1. Sucralfate is an aluminum-containing disaccharide that forms a gel and binds to ulcer beds
2. Misoprostol is a prostaglandin E 1 (PGE 1) analog that promotes healing of ulcers caused by nonsteroidal antiinflammatory drugs (NSAIDs)
B. Indications
1. Sucralfate: Gastric or esophageal ulceration
2. Misoprostol: Prevention and treatment of NSAID-induced gastric and duodenal ulcers
C. Side effects and contraindications
1. Sucralfate binds to many drugs and decreases their bioavailability, particularly doxycycline and fluoroquinolones. Should be given at least 2 hours after other drugs
2. Misoprostol can cause cramping and diarrhea; contraindicated in pregnancy
IV. Prokinetic agents (e.g., metoclopramide, cisapride)
A. Mechanisms
1. Metoclopramide increases gastric and intestinal motility by sensitizing the GI tract to acetylcholine
2. Cisapride has a similar mechanism of action, but also improves colonic motility
3. Metoclopramide (but not cisapride) is also a central antiemetic via inhibition of dopaminergic receptors
B. Indications
1. Gastric atony, ileus, megaesophagus (may reduce reflux)
2. Metoclopramide only: Nausea and vomiting without obstruction
3. Cisapride only: Constipation and megacolon
C. Side effects and contraindications
1. Prokinetic agents are contraindicated in cases of GI obstruction
2. Metoclopramide at high doses can cause tremor. Because of renal elimination, the dose should be reduced in patients with renal insufficiency
3. Cisapride has several drug interactions (e.g. with azole antifungals)
V. Antiemetics: Phenothiazines (e.g., chlorpromazine, prochlorperazine)
A. Mechanisms: Inhibit dopaminergic, cholinergic, and histaminergic receptors to reduce input to the emetic center
B. Indications: Refractory vomiting of defined cause. Use with fluid support
C. Side effects and contraindications: Hypotension, ileus; masks obstruction. Contraindicated in horses because of ataxia and excitation
VI. Antiemetics: Serotonergic antagonists (e.g., ondansetron, dolasteron)
A. Mechanisms: 5-Hydroxytryptamine type 3 (5-HT3) antagonist; blocks input to emetic center
B. Indications
1. Chemotherapy-induced nausea
2. Intractable vomiting and nausea unresponsive to less expensive drugs
C. Side effects and contraindications: Potential to cause CNS signs in collies and other herding dogs with p-glycoprotein defect ( p-glycoprotein substrate)
VII. Antiemetics: Antihistamines
A. Examples: Diphenhydramine (e.g., Benadryl), dimenhydrinate (e.g., Dramamine)
B. Mechanisms
1. H 1 receptor antagonists; block input to emetic center
2. Also have some anticholinergic effects
C. Indications
1. Diphenhydramine: Adjunct to prevent chemotherapy-induced nausea
2. Dimenhydrinate: Motion sickness
D. Side effects and contraindications: Sedation (dogs), excitation or sedation (cats); contraindicated in glaucoma due to anticholinergic effects
VIII. Antidiarrheals: Adsorbents
A. Examples: Bismuth subsalicylate (Pepto-Bismol), kaolin and pectin (Kaopectate)
B. Mechanisms
1. Bismuth has antiendotoxin and weak antibacterial properties; salicylate may reduce secretion in secretory diarrheas
2. Kaolin and pectin are thought to act as adsorbents, with minimal efficacy data
C. Indications
1. Acute diarrhea in dogs, foals, baby pigs
2. Bismuth subsalicylate only: Part of therapy for Helicobacter-associated gastritis
D. Side effects and contraindications
1. May adsorb and impair absorption of other drugs
3. Bismuth subsalicylate will turn stools greenish black
IX. Antidiarrheals: Opioids (e.g., diphenoxylate [Lomotil; also contains atropine], loperamide [Immodium])
A. Mechanism
1. Synthetic opiate agonists, without CNS side effects
2. Increase segmental contractions of gut, but decrease “downstream” movement
3. Increase time available for water resorption and decrease frequency of bowel movements
4. Atropine in Lomotil contributes to decreased motility but primarily is included to decrease abuse potential
B. Indications: Short-term (i.e., less than 48 hours) therapy of acute diarrheas in dogs
C. Side effects: Constipation. Contraindicated for infectious diarrheas ( Salmonella, parvovirus). Opiates not recommended in cats because of excitation
X. Antidiarrheals: Anticholinergics (e.g., aminopentamide [Centrine], propantheline [Pro-Banthine])
A. Mechanisms: Anticholinergic, labeled for use as an antispasmodic antidiarrheal
B. Indications: Not recommended for use in dogs and cats
C. Side effects and contraindications: Can mask signs of disease progression; ileus
XI. Antiinflammatories
A. Salicylate derivatives (e.g., sulfasalazine, olsalazine)
1. Mechanism
a. 5-aminosalicylic acid (5-ASA) linked to a sulfa moiety (sulfasalazine) or another 5-ASA molecule (olsalazine)
b. Cleaved by colonic bacteria to release anti-inflammatory 5-ASA
2. Indications: Chronic inflammatory colitis in dogs; uncommonly used in cats
3. Side effects. Keratoconjunctivitis sicca (KCS; dry eye) in about 15% of dogs given sulfasalazine
B. Glucocorticoids (e.g., prednisone-prednisolone, dexamethasone, budesonide)
1. Indications: Histologic evidence of GI inflammatory infiltrates or lymphangiectasia
2. Budesonide: High first-pass effect, low systemic blood levels. May cause fewer systemic side effects
C. Azathioprine (Imuran)
1. Mechanism
a. Purine analogue that inhibits ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) synthesis
b. Antiinflammatory and immunosuppressive
2. Indications: Lymphangiectasia, refractory or severe inflammatory bowel disease
3. Side effects of azathioprine: Neutropenia, thrombocytopenia, pancreatitis, hepatopathy (increased alanine aminotransferase [ALT]). Not recommended for use in cats because of impaired detoxification of azathioprine
D. Cyclosporine
1. Mechanism
a. Inhibitor of T-cell function
b. Immunosuppressive agent; may deplete T cells
2. Same indications as for azathioprine
3. Side effects of cyclosporine: Vomiting, inappetence, gingival lesions, alopecia, secondary fungal infections
XII. Treatment of constipation
A. Lubricants
1. Petrolatum (e.g., Laxatone)
a. Daily therapy for hairballs
b. May be sufficient for mild constipation in cats
2. Mineral oil: May impair water resorption in colon; risk of aspiration
B. Bulking agents
1. Psyllium (Metamucil)
2. Hemicellulose-containing seed extract
3. Insoluble fiber source; adsorbs water and swells, increasing fecal bulk
C. Osmotics: Lactulose
1. Osmotic laxative; disaccharide of galactose and fructose
2. Nonabsorbable disaccharide which is metabolized by colonic bacteria to release volatile fatty acids. These osmotically active acids draw water into the colon and hydrate colon contents
D. Surfactants: Docusate sodium (DSS)
1. Stool softener; detergent surfactant
2. Emulsifies, hydrates, and softens fecal contents permeability
3. DSS is a mucosal irritant; may increase the absorption of drugs such as digoxin and quinidine
E. Motility enhancers
1. Cisapride: Prokinetic agent related to metoclopramide, but cisapride also acts on smooth muscle of colon
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