Pharmacology PDF - Cardiovascular Drugs

Pharmacology 9 CHA P TE R Lauren A. Trepanier, Katrina R. Viviano, and Sidonie N.Lavergne...

Pharmacology 9 CHA P TE R Lauren A. Trepanier, Katrina R. Viviano, and Sidonie N.Lavergne 1. Metabolized by liver to active drugs (enala- CARDIOVASCULAR DRUGS prilat or benazeprilat). Enalaprilat excreted in I. Diuretics urine; benazeprilat excreted in urine and bile A. Furosemide 2. Mechanism of action 1. Mechanism of action a. Blocks ACE (lungs and vascular endothe- a. Blocks reabsorption of chloride in the loop lium). Prevents the conversion of angioten- of Henle sin I to angiotensin II b. Increases urinary excretion of sodium, chlo- b. An arterial and venous dilator ride, calcium, magnesium, and potassium (1) Decreases total peripheral and pulmo- c. Mild venodilator, shifting fluid from pulmo- nary vascular resistance nary to systemic circulation (2) Decreases systemic blood pressure 2. Indications 3. Indications a. Congestive heart failure (CHF) a. CHF b. Pulmonary edema, pleural effusion, ascites (1) Afterload reduction c. Oliguric renal failure (increases urine flow) (2) Shifts blood from pulmonary to venous d. Hypercalcemia circulation 3. Side effects: Dehydration, prerenal azotemia, b. Hypertension hypokalemia, hypochloremic metabolic acido- c. Protein-losing nephropathy sis; cats more sensitive to adverse effects (1) Decreases glomerular protein loss B. Spironolactone (2) May decrease mesangial cell prolifera- 1. Mechanism of action: Aldosterone antagonist tion and glomerular fibrosis a. Moderate diuretic effect 4. Side effects and contraindications: GI upset, b. Acts in distal renal tubule and collecting hypotension, prerenal azotemia, hyperkalemia ducts (uncommon); contraindicated in dehydration c. Leads to sodium reabsorption, and potas- B. Amlodipine sium and hydrogen secretion 1. Calcium channel blocker that is used as a vaso- 2. Indications dilator, not an antiarrhythmic a. Second-line diuretic for CHF 2. Mechanism of action b. Ascites due to portal hypertension. a. Greatest effect on vascular smooth muscle. Can be used in combination with Peripheral arteriolar vasodilator hydrochlorthiazide b. Little effect on automaticity, conduction 3. Side effects: Hyperkalemia and gastrointestinal velocity of the atrioventricular (AV) or sino- (GI) upset (uncommon) atrial (SA) nodes, or myocardial contractility C. Thiazide diuretics (e.g., hydrochlorthiazide) 3. Indications: Hypertension 1. Mechanism of action 4. Side effects: Negative inotropic effects, hypo- a. Weak diuretic tension (reflex tachycardia) b. Blocks sodium and chloride reabsorption in C. Nitroglycerin the distal tubule 1. Mechanism of action c. Increases calcium reabsorption a. Venodilator d. Decreases potassium and magnesium ab- b. Donor of nitric oxide sorption c. Reduces preload via pulmonary vein dila- 2. Indications: Management of ascites and edema; tion. Shifts blood from pulmonary to venous used in combination with spironolactone system. 3. Side effects: Mild hypokalemia, hypomagnese- 2. Indications: CHF. Topical use (ointment or mia, hypochloremic metabolic alkalosis, hypo- patch) natremia; contraindicated with hypercalcemia 3. Side effects: Hypotension, irritation at site of II. Vasodilators application, tolerance with continued therapy A. Angiotensin-converting enzyme (ACE) inhibitors D. Hydralazine (e.g., enalapril, benazepril). 1. Mechanism of action 94  CHAPTER 9 Pharmacology 95 a. Potent arterial vasodilator and ventricle. Like procainamide, also has b. Direct action on vascular smooth muscle to anticholinergic effects decrease contractility by modification of b. Indications calcium metabolism (1) Atrial fibrillation c. Decreases systemic vascular resistance (a) Direct effect on atrial muscle d. Decreases afterload (b) Anticholinergic effect prolongs 2. Indications: CHF, severe or refractory hyper- atrial refractory period tension (c) Converts atrial fibrillation to normal 3. Side effects: Hypotension, reflex tachycardia, sinus rhythm in horses GI upset (2) Refractory supraventricular E. Prazosin tachycardias 1. Mechanism of action (3) Ventricular arrhythmias a. -1 adrenergic antagonist c. Side effects: GI upset, hypotension, b. Balanced vasodilator worsening of CHF,AV block c. Reduces preload and afterload d. Contraindications: Digoxin toxicity, myas- 2. Indications: CHF, refractory hypertension thenia gravis 3. Side effects: GI upset, syncope (first-dose B. β blockers (Class II antiarrhythmics) effect), development of drug tolerance 1. Mechanisms: Adrenergic receptor antagonists III. Antiarrhythmics a. Decrease sinus heart rate A. Class I (e.g., lidocaine, quinidine, procainamide, b. Increase the refractory period of the AV node mexiletine) c. Decrease myocardial oxygen demand 1. Shared mechanisms of action d. Decrease cardiac inotropy a. Membrane stabilizers 2. Propranolol b. Inhibit fast sodium channels a. Mechanism: Nonselective -adrenergic c. Inhibit the rate of spontaneous depolariza- antagonist; both -1 and -2 receptor tion blockade 2. Lidocaine b. Indications a. Little or no effect on SA or AV nodes or (1) Supraventricular arrhythmias atrial muscle (2) Ventricular arrhythmias b. Indications: Drug of choice to treat life- (3) Hypertrophic and thyrotoxic heart threatening ventricular arrhythmias Not ef- disease fective orally owing to significant first-pass c. Side effects: Negative inotropic effect, bra- hepatic metabolism, intravenous (IV) ad- dycardia, hypotension, decreased hepatic ministration only blood flow (decreases clearance of lido- c. Side effects: Vomiting, central nervous sys- caine), -2 blockade (hypoglycemia, hepatic tem (CNS) signs (ataxia, depression, nystag- receptors; bronchoconstriction, bronchial mus, seizures; treat with diazepam). Use receptors) with caution in patients with hepatic failure; d. Contraindications: Overt heart failure, sinus cats more sensitive to CNS side effects bradycardia, asthma (lower doses used) 3. Atenolol, metoprolol, esmolol 3. Procainamide a. Mechanism of action a. Additional mechanisms (1) -1 adrenergic selective receptor (1) Prolongs refractory period in both the antagonists atria and ventricles (2) Decrease risk of bronchospasm (2) Decreases myocardial excitability b. Indications (3) Anticholinergic effects (1) Supraventricular arrhythmias b. Indications: Used IV for lidocaine-refractory (2) Atenolol drug of choice for feline ventricular arrhythmias arrhythmias c. Side effects and contraindications: GI upset, (3) Hypertrophic and thyrotoxic heart do not use with second- or third- degree AV disease block, drug-induced arrhythmias, may cause (4) Esmolol used IV only (short half life) hypotension with rapid IV administration; c. Side effects: Negative inotropic effect, hypo- contraindicated in myasthenia gravis tension, lethargy, diarrhea 4. Mexiletine d. Contraindications. Bradyarrhythmias a. Oral analogue of lidocaine C. Class III antiarrhythmics b. Indications: Oral drug of choice for ventric- 1. Mechanisms: Block potassium channels ular arrhythmias in dogs a. Prolong the refractory period c. Side effects and contraindications: GI upset. b. Increase the duration of the action potential Do not use with second- or third- degree AV c. Greatest effects in Purkinje fibers and ven- block tricular muscle 5. Quinidine 2. Sotalol a. Prolongs the duration of the action poten- a. Combination class II and class III antiar- tial and refractory period in both the atria rhythmic 96 SECTION I GENERAL DISCIPLINES IN VETERINARY MEDICINE (1) Nonselective -adrenergic receptor (resulting from systemic vasodilation); antagonist heart block (2) Potassium channel blocker f. Contraindications: Use with -adrenergic an- b. Indications: Refractory ventricular arrhyth- tagonists, hypotension, sick sinus syn- mias; boxer arrhythmias drome, second- or third-degree heart block c. Side effects: Drug-drug interactions, nega- IV. Adrenergic agonists tive inotropy, proarrhythmic, broncho- A. Dobutamine spasm, GI upset 1. Mechanism of action d. Contraindications: Asthma, sinus bradycar- a. Synthetic catecholamine dia, second- or third-degree heart block b. Direct -1 agonist with mild -2 and -1 3. Amiodarone adrenergic effects a. Mechanism of action (1) Increased myocardial contractility and (1) Structural analogue of thyroid hormone output (2) Inhibits  and  receptors (nonselec- (2) Minimal effects on systemic blood pres- tive, noncompetitive) sure or heart rate (3) Inhibits sodium and calcium channels 2. Indications: Cardiogenic shock; intended for (4) Prolongs action potential duration and short-term use (48 to 72 hours) refractory period 3. Side effects: -1 receptor desensitization oc- b. Indications. Reserved for refractory curs with prolonged use, ectopic beats, in- ventricular tachycardia creased heart rate or blood pressure c. Side effects: Many drug interactions, B. Dopamine GI upset, neutropenia, hepatotoxicity 1. Mechanism of action d. Contraindications: Second- and third-degree a. Endogenous catecholamine that acts on - AV block, bradyarrhythmias and -adrenergic receptors and dopamine D. Calcium channel blockers (class IV receptors antiarrhythmics) b. Positive inotrope; stimulation of cardiac -1 1. Mechanism receptors a. Block influx of calcium through slow c. Pharmacological effects are dose dependent calcium channels during plateau of action (1) Low dose (2 g/kg/min): Stimulates do- potential paminergic receptors to increase mes- b. Slow SA and AV node conduction enteric, coronary, and renal blood flow c. Decrease vascular smooth-muscle contrac- (2) Moderate dose (5 g/kg/min): Cardiac tility. Systemic and coronary vasodilation -1 adrenergic stimulation, producing d. Decrease myocardial contractility (negative increased cardiac output with minimal inotropy) effects of peripheral vasculature 2. Diltiazem (3) High dose (10 g/kg/min); Stimulates a. Slows AV conduction velocity and prolongs -adrenergic receptors producing pe- refractory period (rarely affects SA node ripheral vasoconstriction and increased conduction) blood pressure b. Minimal effect on cardiac contractility 2. Indications: Refractory hypotension; acute c. Mild peripheral vasodilation renal failure d. Indications 3. Side effects: Tachycardia, arrhythmias, in- (1) Supraventricular tachyarrhythmias creased myocardial oxygen demand (atrial fibrillation) 4. Contraindications: Pheochromocytoma, (2) Hypertrophic cardiomyopathy (cats) ventricular fibrillation, uncorrected e. Side effects: Bradycardia (dogs), GI upset tachyarrhythmia (cats), hypotension, arrhythmias V. Digoxin f. Contraindications: Potentiate the negative A. Mechanism of action inotropic and chronotropic effects of 1. Mild positive inotrope. Inhibits Na/K/ATPase -adrenergic antagonists; severe hypoten- pump, promoting Na/Ca exchange and increas- sion, sick sinus syndrome, second- or ing intracellular calcium concentrations third-degree AV block 2. Slows rapid ventricular rates; increases para- 3. Verapamil sympathetic tone a. Pronounced effect on AV node 3. Neurohormonal modulation. Reduces plasma (1) Increased refractory period levels of norepinephrine, aldosterone, renin (2) Decreased automaticity and AV B. Indications conduction 1. CHF (decreased contractility): Dilated b. Clinically significant negative inotropy cardiomyopathy or valvular disease c. Decreased peripheral vascular resistance 2. Supraventricular tachycardia (atrial d. Indications: Supraventricular tachyarrhyth- fibrillation) mias C. Side effects e. Side effects: Increased blood levels of 1. Digoxin toxicity (narrow therapeutic range). digoxin and theophylline; hypotension Therapeutic drug monitoring recommended  CHAPTER 9 Pharmacology 97 2. Extracardiac: GI upset, muscle weakness, C. Side effects: CNS signs (excitement, seizures, rest- depression, disorientation lessness), GI upset, polyuria, polydipsia. Narrow 3. Cardiac: Partial or complete heart block, therapeutic range ventricular arrhythmias D. Contraindications: Cardiac arrhythmias, hyper- 4. Many drug interactions tension, gastric ulcers, renal or hepatic disease, VI. Phosphodiesterase inhibitors hyperthyroidism A. Mechanisms II. -2 adrenergic agonists 1. Positive inotropes or vasodilators A. Mechanisms 2. Inhibit phosphodiesterase type III (cardiac- 1. Relaxation of bronchial smooth muscle specific phosphodiesterase) a. Activation of -2 adrenergic receptors a. Increased intracellular cAMP b. Increased cAMP via activation of adenyl b. Increased myocardial contractility cyclase 3. Arteriodilation and venodilation (both pulmo- (1) Activation of protein kinase A (broncho- nary and systemic vasculature) dilation) 4. Potentiate adrenergic signal transduction (2) Inhibition of inflammatory cell mediator a. Increases myocardial contractility (positive release inotrope) 2. Stimulate secretion of mucus b. Increases myocardial relaxation 3. Enhance mucociliary clearance 5. Enhanced cardiac contractility without in- B. Terbutaline, albuterol creased myocardial oxygen consumption 1. Selective -2 adrenergic receptor agonists B. Pimobendan. 2. Indications: Bronchospasm. Albuterol available 1. Additional mechanisms as inhaler a. Potentiates adrenergic signal transduction 3. Side effects: Tremors, tachycardia, CNS excite- (positive inotrope; increases myocardial ment (secondary to nonspecific -1 receptor relaxation) activation at high doses) b. Enhanced cardiac contractility without 4. Contraindications: Cardiac arrhythmias, hyper- increased myocardial oxygen tension, seizures, hyperthyroidism. Use with consumption caution 2. Indications: CHF, dilated cardiomyopathy or C. Epinephrine valvular disease 1. Nonselective - adrenergic agonists. Stimulates 3. Side effects: Arrhythmias, mild GI upset -1, -2, and -adrenergic receptors C. Amrinone, milrinone 2. Indications 1. Indications a. Allergic reactions (insect bites, urticaria) a. CHF (decreased contractility). Dilated b. Acute severe bronchospasm cardiomyopathy or valvular disease 3. Side effects: Tachycardia, vasoconstriction, b. Arterial hypertension hypertension (result of -1 and - adrenergic c. Milrinone is 10 to 20 times more potent receptor activation) 2. Side effects: Arrhythmias, GI upset, thrombocy- III. Opioid cough suppressants topenia, hepatotoxicity, fever A. Butorphanol 1. Mechanism of action a. Synthetic opioid PULMONARY DRUGS b. Mixed agonist-antagonist: -receptor ago- I. Methylxanthines (e.g., theophylline, aminophylline nist, weak -receptor antagonist [theophylline ethylenediamine salt; 80% theophylline]) c. Suppresses afferent input into coughing A. Mechanisms of action center (medulla) 1. Direct smooth muscle relaxation of bronchi 2. Indications: Antitussive in dogs with minimal and pulmonary vasculature (bronchodilation to no sedation; mild analgesia and vasodilation) 3. Side effects: Sedation (higher doses); signifi- 2. Competitive inhibition of phosphodiesterase: cant hepatic first-pass effect (requires higher Increases cAMP levels, which increase endoge- oral dosing). Minimal cardiac and respiratory nous epinephrine depression 3. Competitive antagonism of adenosine B. Hydrocodone 4. Interference with calcium mobilization 1. Mechanism of action 5. Other effects a. Opioid agonist a. Inhibit histamine release (inhibition of mast b. Suppression of afferent input into coughing cell degranulation) and inflammatory media- center (medulla) tor release c. Drying effect on respiratory mucosa b. Increase mucociliary clearance 2. Indications: Antitussive in dogs c. Prevent microvascular leakage 3. Side effects: Sedation, respiratory and cardiac d. Increase strength of respiratory depression, constipation muscles IV. Inhaled glucocorticoids: Fluticasone B. Indications: Bronchospasm. Extended released A. Mechanism of action formulations available 1. Trifluorinated glucocorticoid 98 SECTION I GENERAL DISCIPLINES IN VETERINARY MEDICINE 2. Potent antiinflammatory activity 2. Metoclopramide only: Nausea and vomiting 3. High topical potency without obstruction 4. Low systemic bioavailability 3. Cisapride only: Constipation and megacolon 5. Bronchodilation C. Side effects and contraindications B. Indications: Allergic airway disease and feline 1. Prokinetic agents are contraindicated in cases asthma of GI obstruction C. Side effects: Suppression of hypothalamic-pituitary- 2. Metoclopramide at high doses can cause tremor. adrenal (HPA) axis; contraindicated with acute Because of renal elimination, the dose should be bronchospasm reduced in patients with renal insufficiency 3. Cisapride has several drug interactions (e.g. with azole antifungals) GASTROINTESTINAL (GI) DRUGS V. Antiemetics: Phenothiazines (e.g., chlorpromazine, I. Histamine type 2 (H2) blockers (e.g, cimetidine, ranit- prochlorperazine) idine, famotidine) A. Mechanisms: Inhibit dopaminergic, cholinergic, A. Mechanism: Inhibit H2 receptors in gastric pari- and histaminergic receptors to reduce input to etal cells, blocking HCl secretion. Ranitidine may the emetic center also have some prokinetic activity B. Indications: Refractory vomiting of defined cause. B. Indications: Reflux esophagitis, gastric ulcers, Use with fluid support mast cell tumors, vomiting from liver or renal C. Side effects and contraindications: Hypotension, disease ileus; masks obstruction. Contraindicated in C. Side effects and contraindications: Cimetidine is a horses because of ataxia and excitation P450 inhibitor and decreases clearance of many VI. Antiemetics: Serotonergic antagonists drugs, leading to drug interactions (e.g., ondansetron, dolasteron) II. Pump blockers (e.g., omeprazole) A. Mechanisms: 5-Hydroxytryptamine type 3 (5-HT3) A. Mechanisms: Proton pump inhibitor; inhibits antagonist; blocks input to emetic center NH/K ATPase and inhibits HCl secretion in B. Indications gastric parietal cells 1. Chemotherapy-induced nausea B. Indications: Reflux esophagitis, severe gastric ul- 2. Intractable vomiting and nausea unresponsive cers, mast cell tumors, gastrinoma to less expensive drugs C. Side effects and contraindications: Omeprazole is C. Side effects and contraindications: Potential to a P450 inhibitor and decreases the clearance of cause CNS signs in collies and other herding dogs some drugs in people with p-glycoprotein defect (p-glycoprotein III. Gastroprotectants (e.g., sucralfate, misoprostol) substrate) A. Mechanisms VII. Antiemetics: Antihistamines 1. Sucralfate is an aluminum-containing disaccha- A. Examples: Diphenhydramine (e.g., Benadryl), ride that forms a gel and binds to ulcer beds dimenhydrinate (e.g., Dramamine) 2. Misoprostol is a prostaglandin E1 (PGE1) analog B. Mechanisms that promotes healing of ulcers caused by non- 1. H1 receptor antagonists; block input to emetic steroidal antiinflammatory drugs (NSAIDs) center B. Indications 2. Also have some anticholinergic effects 1. Sucralfate: Gastric or esophageal ulceration C. Indications 2. Misoprostol: Prevention and treatment of 1. Diphenhydramine: Adjunct to prevent NSAID-induced gastric and duodenal ulcers chemotherapy-induced nausea C. Side effects and contraindications 2. Dimenhydrinate: Motion sickness 1. Sucralfate binds to many drugs and decreases D. Side effects and contraindications: Sedation their bioavailability, particularly doxycycline (dogs), excitation or sedation (cats); contraindi- and fluoroquinolones. Should be given at least cated in glaucoma due to anticholinergic effects 2 hours after other drugs VIII. Antidiarrheals: Adsorbents 2. Misoprostol can cause cramping and diarrhea; A. Examples: Bismuth subsalicylate (Pepto-Bismol), contraindicated in pregnancy kaolin and pectin (Kaopectate) IV. Prokinetic agents (e.g., metoclopramide, cisapride) B. Mechanisms A. Mechanisms 1. Bismuth has antiendotoxin and weak antibac- 1. Metoclopramide increases gastric and terial properties; salicylate may reduce secre- intestinal motility by sensitizing the GI tract tion in secretory diarrheas to acetylcholine 2. Kaolin and pectin are thought to act as adsor- 2. Cisapride has a similar mechanism of action, bents, with minimal efficacy data but also improves colonic motility C. Indications 3. Metoclopramide (but not cisapride) is also a 1. Acute diarrhea in dogs, foals, baby pigs central antiemetic via inhibition of dopaminer- 2. Bismuth subsalicylate only: Part of therapy for gic receptors Helicobacter-associated gastritis B. Indications D. Side effects and contraindications 1. Gastric atony, ileus, megaesophagus (may re- 1. May adsorb and impair absorption of other duce reflux) drugs  CHAPTER 9 Pharmacology 99 2. Pepto-Bismol and newer formulations of Kao- D. Cyclosporine pectate contain salicylate, which should be 1. Mechanism used with caution in cats a. Inhibitor of T-cell function 3. Bismuth subsalicylate will turn stools greenish b. Immunosuppressive agent; may deplete black T cells IX. Antidiarrheals: Opioids (e.g.,diphenoxylate [Lomotil; 2. Same indications as for azathioprine also contains atropine], loperamide [Immodium]) 3. Side effects of cyclosporine: Vomiting, inappe- A. Mechanism tence, gingival lesions, alopecia, secondary 1. Synthetic opiate agonists, without CNS side fungal infections effects XII. Treatment of constipation 2. Increase segmental contractions of gut, but A. Lubricants decrease “downstream” movement 1. Petrolatum (e.g., Laxatone) 3. Increase time available for water resorption a. Daily therapy for hairballs and decrease frequency of bowel movements b. May be sufficient for mild constipation 4. Atropine in Lomotil contributes to decreased in cats motility but primarily is included to decrease 2. Mineral oil: May impair water resorption in abuse potential colon; risk of aspiration B. Indications: Short-term (i.e., less than 48 hours) B. Bulking agents therapy of acute diarrheas in dogs 1. Psyllium (Metamucil) C. Side effects: Constipation. Contraindicated for infec- 2. Hemicellulose-containing seed extract tious diarrheas (Salmonella, parvovirus). Opiates 3. Insoluble fiber source; adsorbs water and not recommended in cats because of excitation swells, increasing fecal bulk X. Antidiarrheals: Anticholinergics (e.g., aminopentamide C. Osmotics: Lactulose [Centrine], propantheline [Pro-Banthine]) 1. Osmotic laxative; disaccharide of galactose A. Mechanisms: Anticholinergic, labeled for use as and fructose an antispasmodic antidiarrheal 2. Nonabsorbable disaccharide which is metabo- B. Indications: Not recommended for use in dogs lized by colonic bacteria to release volatile and cats fatty acids. These osmotically active acids C. Side effects and contraindications: Can mask draw water into the colon and hydrate colon signs of disease progression; ileus contents XI. Antiinflammatories D. Surfactants: Docusate sodium (DSS) A. Salicylate derivatives (e.g., sulfasalazine, 1. Stool softener; detergent surfactant olsalazine) 2. Emulsifies, hydrates, and softens fecal con- 1. Mechanism tents permeability a. 5-aminosalicylic acid (5-ASA) linked to a 3. DSS is a mucosal irritant; may increase the ab- sulfa moiety (sulfasalazine) or another sorption of drugs such as digoxin and quinidine 5-ASA molecule (olsalazine) E. Motility enhancers b. Cleaved by colonic bacteria to release anti- 1. Cisapride: Prokinetic agent related to metoclo- inflammatory 5-ASA pramide, but cisapride also acts on smooth 2. Indications: Chronic inflammatory colitis in muscle of colon dogs; uncommonly used in cats 2. Bisacodyl (Dulcolax): Increases water permea- 3. Side effects. Keratoconjunctivitis sicca (KCS; dry bility of mucosal cells (may alter tight junc- eye) in about 15% of dogs given sulfasalazine tions); increases electrolyte flux to lumen, B. Glucocorticoids (e.g., prednisone-prednisolone, probably by inhibiting Na/K ATPase; may dexamethasone, budesonide) increase secretion and motility 1. Indications: Histologic evidence of GI inflamma- tory infiltrates or lymphangiectasia DRUGS FOR HEPATIC DISEASE 2. Budesonide: High first-pass effect, low sys- temic blood levels. May cause fewer systemic I. Hepatoprotectants side effects A. Ursodiol C. Azathioprine (Imuran) 1. Mechanisms: Increases bile flow (choleretic); 1. Mechanism may reduce hepatotoxic effects of bile salts a. Purine analogue that inhibits ribonucleic 2. Indications: Inflammatory and cholestatic liver acid (RNA) and deoxyribonucleic acid diseases in dogs and cats (DNA) synthesis 3. Side effects and contraindications: Contraindi- b. Antiinflammatory and immunosuppressive cated with biliary obstruction 2. Indications: Lymphangiectasia, refractory or B. S-adenosylmethionine severe inflammatory bowel disease 1. Mechanisms: Glutathione precursor; may have 3. Side effects of azathioprine: Neutropenia, other hepatoprotective effects thrombocytopenia, pancreatitis, hepatopathy 2. Indications (increased alanine aminotransferase [ALT]). a. Hepatic inflammation and necrosis in dogs Not recommended for use in cats because of and cats impaired detoxification of azathioprine b. Acetaminophen toxicosis 100 SECTION I GENERAL DISCIPLINES IN VETERINARY MEDICINE 3. Side effects and contraindications: Possible a. Used empirically for hepatopathies adverse interaction with tricyclic associated with mild to moderate copper antidepressants accumulation C. Silymarin (milk thistle extract) b. Used empirically for mild to moderate 1. Mechanisms: May have antioxidant properties; fibrosis may have antiinflammatory properties via inhi- 3. Side effects and contraindications: GI upset; bition of 5-lipoxygenase high plasma zinc levels lead to hemolysis 2. Indications: Empirical treatment of hepatic inflammation and necrosis in dogs and cats DRUGS FOR ENDOCRINE DISEASE 3. Side effects and contraindications: Formula- tions may vary in content and potency I. Thyroid disease (over-the-counter [OTC] nutraceutical) A. Methimazole II. Drugs for hepatic encephalopathy 1. Mechanism: Inhibits thyroid peroxidase and A. Lactulose thyroid hormone synthesis 1. Mechanism: Converted to osmotically active 2. Indications: Medical management of acids in colon; traps ammonia and reduces its hyperthyroidism absorption. Acts as osmotic cathartic 3. Side effects and contraindications: GI upset 2. Indications: Hepatic encephalopathy; also (dose dependent); idiosyncratic reactions constipation (facial excoriation, thrombocytopenia, neutro- 3. Side effects and contraindications: penia, hepatopathy); treatment can unmask Dose-dependent diarrhea underlying renal disease B. Neomycin B. Radioiodine 1. Mechanisms: Inhibits ammonia generation in 1. Mechanisms: Actively captured by thyroid colon; poorly absorbed aminoglycoside used glands; destroys active thyroid tissue via local orally β irradiation 2. Indications: Hepatic encephalopathy 2. Indications: Hyperthyroidism (generally 3. Side effects and contraindications: Bitter curative) taste 3. Side effects and contraindications: Requires C. Metronidazole short quarantine; treatment can unmask un- 1. Mechanisms: Kills ammonia-producing anaer- derlying renal disease obes in colon C. L-thyroxine 2. Indications: Hepatic encephalopathy; also used 1. Mechanisms: Physiologic replacement of T4 for anaerobic infections 2. Indications: Hypothyroidism 3. Side effects and contraindications: Cerebell- 3. Side effects and contraindications: Excess dose ovestibular neurologic signs with overdose; an- can lead to tremor, tachycardia, weight loss. orexia, GI upset Bioavailability varies; monitor with post-pill III. Antifibrotics: Colchicine (4 to 6 hours) thyroid hormone concentrations A. Mechanisms II. Drugs for adrenal disease 1. Microtubule inhibitor A. Hyperadrenocorticism 2. Inhibits procollagen secretion 1. Mitotane B. Indications: Used empirically for fibrotic liver dis- a. Mechanisms ease with or without ascites (1) Toxic to zona fasciculata and zona retic- C. Side effects and contraindications: GI upset (dose ularis layers of the adrenal glands dependent); peripheral neuropathy, myopathy, (2) Decreases glucocorticoid secretion and bone marrow suppression less common b. Indications IV. Decoppering agents (1) Pituitary dependent hyperadrenocorti- A. D-penicillamine cism in dogs 1. Mechanisms (2) At high doses, treatment of inoperable a. Chelates plasma copper to allow urinary glucocorticoid-secreting adrenal excretion tumors b. May also inhibit hepatic fibrosis c. Side effects and contraindications: Direct 2. Indications. Biopsy diagnosis of copper- GI upset; hypocortisolemia with resulting associated hepatopathy lethargy and GI upset. Generally spares 3. Side effects: GI upset (common); contraindi- aldosterone-secreting zona glomerulosa cated in pregnancy unless very high doses used B. Zinc 2. Trilostane 1. Mechanisms a. Mechanisms a. Decreases copper absorption (1) Inhibits adrenal enzyme b. Induces metallothionein synthesis by en- 3-beta-hydroxysteroid dehydrogenase terocytes, which binds intestinal copper (2) Decreases cortisol and aldosterone and prevents absorption secretion c. May also have antifibrotic effects b. Indications: Pituitary dependent hyperadre- 2. Indications nocorticism in dogs  CHAPTER 9 Pharmacology 101 c. Side effects and contraindications: Hypocor- (1) Slowly absorbed, longer acting tisolemia with resulting lethargy and GI up- (2) Subcutaneously or IM only set; hyponatremia and hyperkalemia (3) PZI suitable for twice (or sometimes B. Hypoadrenocorticism once) daily maintenance administration, 1. Mineralocorticoid supplementation in cats especially a. Desoxycorticosterone pivalate (DOCP) d. Glargine (1) Mechanism: Long-acting injectable min- (1) Slowly absorbed, longer acting eralocorticoid given about every 25 to (2) SQ or IM only 28 days (3) Fairly flat glucose curve (2) Indications: Hypoadrenocorticism with (4) Glargine suitable for twice (or some- hyponatremia or hyperkalemia times once) daily maintenance adminis- (3) Side effects and contraindications tration, in cats especially (a) Dose and dosing interval must 2. Side effects and contraindications: Hypoglyce- be adjusted based on serum mia (weakness, twitching, seizures) electrolytes B. Oral hyoglycemics: Glipizide (b) No glucocorticoid activity; requires 1. Mechanisms adjunct use of glucocorticoids for a. Enhances insulin secretion by pancreatic treatment of hypoadrenocorticism -cells b. Fludrocortisone b. May enhance peripheral sensitivity to (1) Short-acting oral mineralocorticoid insulin (2) Given daily 2. Indications: Nonketotic, mild diabetes in cats (3) Indicated as for DOCP 3. Side effects and contraindications: Lack of effi- (4) Has some glucocorticoid activity cacy, hypoglycemia, GI upset, increased ALT (5) May cause unacceptable polyuria and (reversible) polydipsia at doses required to normal- ize sodium and potassium DRUGS FOR RENAL DISEASE 2. Prednisone a. Mechanisms: Precursor of prednisolone I. Drugs to promote diuresis with cortisol-like effects A. Mannitol b. Indications: Used for physiologic replace- 1. Mechanism of action: Osmotic diuretic ment of cortisol in hypoadrenocorticism 2. Indications c. Side effects and contraindications: Polyuria, a. Nonobstructive oliguric renal failure polydipsia, panting, increased risk of infec- b. Promote diuresis in some toxicoses tion, muscle wasting, insulin resistance c. Also used for glaucoma, increased intracra- 3. Dexamethasone nial pressure a. Mechanisms 3. Side effects: Nausea, dizziness, volume over- (1) 6 to 10 times more potent than load, hyponatremia, hypokalemia prednisone 4. Contraindications: Dehydration, active intra- (2) No mineralocorticoid activity cranial bleeding, hypertension, pulmonary b. Indications edema (1) Substituted for prednisone or B. Dopamine prednisolone when sodium retention is 1. Mechanism of action a concern a. Endogenous catecholamine: Immediate pre- (2) Does not interfere with cortisol assay cursor of norepinephrine (unlike prednisone or prednisolone) b. At low doses: Binding to dopamine recep- c. Side effects and contraindications: Polyuria, tors leads to renal vasodilation polydipsia, panting, increased risk of infec- 2. Indications. Sometimes used for oliguric renal tion, muscle wasting, insulin resistance failure; efficacy is controversial III. Drug for diabetes mellitus 3. Side effects: Nausea, vomiting, tachycardia, A. Insulins arrhythmias at higher doses 1. Indications 4. Contraindications: Pheochromocytoma, a. Regular ventricular fibrillation, tachyarrhythmias (1) Most rapid onset and shortest acting II. ACE inhibitors (e.g., enalapril, benazepril) (2) Can be given IV, subcutaneously (SQ), A. Mechanisms or intramuscularly (IM) 1. Inhibit ACE to decrease generation of (3) Used for short-term management of angiotensin II diabetics during hospitalization 2. Secondarily decreases elaboration of aldoste- b. NPH, Lente rone and antidiuretic hormone (ADH) (1) Intermediate acting B. Indications (2) SQ or IM only 1. Hypertension, particularly that associated with (3) Suitable for twice daily maintenance renal failure administration 2. Protein-losing nephropathy, to reduce c. PZI, Ultralente proteinuria 102 SECTION I GENERAL DISCIPLINES IN VETERINARY MEDICINE C. Side effects and contraindications: GI upset; may 2. In case of overdose, bronchospasm, bradycar- exacerbate azotemia (if dose leads to hypoten- dia can result sion); may worsen hyperkalemia D. Contraindications: Urinary obstruction, bladder III. Potassium (e.g., potassium gluconate, potassium rupture, asthma citrate, potassium chloride [KCl]) III. Amitriptyline A. Mechanisms A. Mechanism of action: Tricyclic antidepressant 1. K supplementation (principal intracellular cation) 1. Blocks serotonin and norepinephrine reuptake a. Cell tonicity 2. Central sedative b. Cell resting membrane potential 3. Central and peripheral anticholinergic activity c. Muscle contractility B. Indications 2. K citrate is also an alkalinizing agent. Citrate 1. Spraying in cats oxidized to bicarbonate 2. Interstitial cystitis in cats B. Indications 3. Separation anxiety 1. Hypokalemia C. Side effects: Sedation, ataxia, paradoxical hyper- 2. K citrate only excitability, urinary retention a. Urine alkalinization (e.g., reduce risk of cal- D. Contraindications. Concomitant use of monamine cium oxalate uroliths) oxidase (MAO) inhibitors b. Metabolic acidosis associated with chronic IV. Phenylpropanolamine renal failure A. Mechanism of action. Primarily an -adrenergic C. Side effects: GI upset; hyperkalemia (if over- agonist dosed); alkalosis (potassium citrate) B. Indications D. Contraindications: Oliguria or anuria 1. Incontinence owing to decreased internal ure- IV. EPO (human recombinant erythropoietin) thral sphincter tone A. Mechanism of action: Stimulates erythropoiesis 2. Nasal congestion 1. Increases differentiation and proliferation of C. Side effects: Restlessness, irritability, sedation, red blood cell (RBC) precursors hypertension, anorexia 2. Released in response to renal hypoxia D. Contraindications (relative): Glaucoma, hyperten- B. Indications: Anemia of chronic renal failure or due sion, untreated hyperthyroidism, benign prostatic to cancer chemotherapy hypertrophy C. Side effects: AntiEPO antibodies common in dogs V. DES (diethylstilbestrol) and cats (will lead to arrest of erythropoiesis); A. Mechanism of action: Synthetic estrogen hypertension, seizures, iron deficiency, B. Indications: Hormone-responsive (“spay”) inconti- dose-dependent polycythemia. Risk of antibodies nence in dogs may be lower with darbepoietin C. Side effects: Bone marrow suppression at high D. Contraindications: Untreated hypertension, doses, estrus, pyometra at high doses; femininiza- preexisting iron deficiency tion of males D. Contraindications (absolute): Food animals; pregnancy DRUGS FOR LOWER URINARY TRACT DISEASE ANTIBACTERIALS I. Phenoxybenzamine A. Mechanism of action.  adrenergic blocker. Relax- I. Penicillins ation of internal urethral sphincter A. Examples B. Indications 1. Penicillin G, amoxicillin, ampicillin, amoxicillin- 1. Urethrospasm clavulanate, ampicillin-sulbactam 2. Laminitis in horses 2. Extended spectrum: ticarcillin, carbenicillin 3. Pheochromocytoma with hypertension B. Mechanisms C. Side effects: Hypotension, rebound tachycardia, 1. Inhibit bacterial cell-wall synthesis weakness, dizziness, GI distress (constipation in 2. Susceptible to -lactamases unless formulated horses), increased intraocular pressure, inhibi- with -lactamase inhibitors such as clavula- tion of ejaculation nate or sulbactam D. Contraindications: Hypotension, equine colic, C. Spectrum glaucoma 1. Standard penicillins: Good anaerobic spec- II. Bethanechol trum; some gram-positive and gram-negative A. Mechanism of action: Cholinergic agonist spectrum; spirochetes (Leptospira, Borrelia) 1. Mainly muscarinic receptors; nicotinic signs 2. Extended-spectrum penicillins: Expanded only if overdose gram-negative, often including Pseudomonas 2. Increases bladder detrusor tone D. Side effects and contraindications: GI upset com- B. Indications: Urinary retention without obstruction mon (oral use); penicillin allergy uncommon (detrusor atony) II. Cephalosporins C. Side effects A. Examples: 1. SLUD: Salivation, lacrimation, urination, 1. First generation: Cephalexin, cephalothin, defecation cefazolin, cephadroxil  CHAPTER 9 Pharmacology 103 2. Second generation: Cefoxitin, cefotetan 2. Sulfonamides: False folate analogues 3. Third generation: Ceftazidime, ceftiaxone. B. Indications: Some gram-negatives, Nocardia, Cefpodoxime classified as third generation but Pneumocystis does not have typical expanded spectrum C. Side effects and contraindications B. Mechanisms 1. KCS 1. Inhibit bacterial cell-wall synthesis 2. Idiosyncratic reactions (blood dyscrasias, 2. Less sensitive to -lactamases than are hepatotoxicity, arthropathy, skin eruptions) penicillins 3. May precipitate out in acid urine and cause C. Spectrum hematuria 1. First generation: Excellent gram-positive VI. Aminoglycosides (e.g., gentamicin, amikacin) spectrum; lesser gram-negative spectrum; A. Mechanisms most anaerobes susceptible. Enterococcus 1. Inhibit protein synthesis not susceptible 2. Bind to ribosomal 30S subunit 2. Second generation: Extended gram-negative 3. Require energy for bacterial uptake coverage, plus Bacteroides B. Indications: Serious gram-negative infections; no 3. Third generation: Greatly extended spectrum for anaerobes gram-negative coverage C. Side effects and contraindications: Dose D. Side effects and contraindications: GI upset; poor dependent nephrotoxicity (monitor daily urine CNS and prostate penetration sediments for granular casts); dose-dependent III. Fluoroquinolones (Examples: Enrofloxacin, orbifloxa- ototoxicity cin, marbofloxacin, difloxacin, ciprofloxacin) VII. Metronidazole A. Mechanisms: Inhibits DNA gyrase, preventing bac- A. Mechanisms: Converted under anerobic condi- terial DNA synthesis tions to a metabolite that is thought to disrupt B. Indications bacterial DNA synthesis 1. Many gram-negatives, Staphylococcus B. Indications 2. Mycoplasma, Brucella 1. Anaerobic infections 3. Good penetration of CNS, eye, and prostate 2. Some efficacy for Giardia and Entamoeba 4. No anaerobic spectrum infections C. Side effects and contraindications 3. Used as part of “triple therapy” for Helico- 1. Cartilage damage in growing animals (espe- bacter infection in some protocols cially dogs) 4. Used as adjunct therapy in the treatment of in- 2. Retinal toxicity and blindness with modest flammatory bowel disease overdose in cats (enrofloxacin  orbifloxacin C. Side effects and contraindications: Cerebelloves-  marbifloxacin) tibular neurologic signs with overdose; anorexia, 3. May exacerbate seizure disorders GI upset 4. Poorly absorbed orally with cations (iron, VIII. Macrolides (e.g., erythromycin, azithromycin, calcium, zinc, bismuth, aluminum-containing tylosin) drugs) A. Mechanisms: Inhibits protein synthesis; binds to IV. Tetracyclines (e.g., tetracycline, oxytetracyline, 50S ribosomal subunit doxycycline) B. Indications A. Mechanisms inhibit protein synthesis; bind to 1. Erythromycin, azithromycin 30S and 50S ribosomal subunits a. Anaerobes and gram-positive aerobes B. Indications b. Chlamydia, Mycoplasma spp. 1. Rickettsial, Anaplasma, and Mycoplasma 2. Tylosin infections a. Used for colitis in dogs and cats 2. Brucella, Chlamydia organisms b. Used in cattle for bovine respiratory 3. Spirochetes (Leptospira, Borrelia) disease complex C. Side effects and contraindications C. Side effects and contraindications: Tylosin 1. Tooth enamel discoloration contraindicated in horses (may cause colitis) 2. Increase in blood urea nitrogen (BUN; cata- IX. Lincosamides (e.g., clindamycin) bolic effect) A. Mechanisms: inhibits protein synthesis; binds to 3. Diarrhea, intestinal superinfections 50S ribosomal subunit 4. Outdated tetracyclines can cause renal proxi- B. Indications mal tubular toxicity 1. Toxoplasma 5. Poorly absorbed orally with cations (iron, cal- 2. Mycoplasma, Chlamydia cium, zinc, bismuth, aluminum-containing drugs) 3. Anaerobes and gram-positive aerobes V. Potentiated sulfonamides (e.g., trimethoprim- C. Side effects and contraindications: GI upset; sulfadiazine, ormetoprin-sulfadimethoxine, esophageal strictures reported in cats given trimethoprim-sulfamethoxazole) clindamycin capsules A. Mechanisms X. Chloramphenicol and derivatives (e.g., chloramphen- 1. Trimethoprim, ormetoprim: Inhibit dihydrofo- icol, florfenicol) late reductase and decrease folate synthesis in A. Mechanisms: Inhibits protein synthesis; binds to susceptible bacteria 50S ribosomal subunit 104 SECTION I GENERAL DISCIPLINES IN VETERINARY MEDICINE B. Spectrum and indications a. Taken up well by organs of the mononuclear 1. Anaerobes phagocyte system (liver, spleen, and lungs) 2. Good penetration of CNS, prostate b. Decreased nephrotoxicity 3. Florfenicol only: Treatment of Pasteurella and 3. Indications are systemic mycoses. Aspergillus Haemophilus pneumonias in cattle is usually resistant. C. Side effects and contraindications 4. Side effects and contraindications 1. Dose-dependent bone marrow suppression a. Administration limited to IV use 2. Chloramphenicol prohibited in food-producing b. Nephrotoxicity (direct toxic effect on renal animals because of rare idiosyncratic aplastic tubular epithelium; renal vasoconstriction anemia in humans decreases glomerular filtration rate [GFR]) 3. Chloramphenicol inhibits the metabolism of c. Fever and vomiting barbiturates such as phenobarbital and en- d. Anaphylaxis hances their effects e. Do not use with concurrent renal or hepatic XI. Rifampin failure A. Mechanisms: Inhibits DNA-dependent RNA f. Do not use with aminoglycosides or NSAIDs polymerase B. Griseofulvin B. Spectrum and indications: Mycobacteria, Rhodo- 1. Mechanism of action coccus equi a. Enters fungi through an energy-dependent C. Side effects and contraindications: Leads to mechanism orange color to urine, saliva, tears, sweat; Rapid b. Binds to polymerized microtubules and dis- resistance when used alone rupts mitosis. Accumulates in developing keratinocytes and remains in mature kerati- nocytes until shed ANTIFUNGALS 2. Indications: Active against dermatophytes I. Azole antifungals (e.g., ketoconazole, itraconazole, (Microsporum and Trichophyton); no effect fluconazole, clotrimazole) against yeast A. Mechanisms: Block synthesis of ergosterol, an im- 3. Side effects and contraindications portant component of fungal cytoplasmic mem- a. Cats and particularly kittens have increased brane (ergosterol is not present in mammalian risk of: GI upset, bone marrow suppression, cell membranes) neurotoxicity, hepatotoxicity B. Indications b. Teratogenic in cats 1. Ketoconazole and itraconazole used for derma- tophytes, Blastomyces, Coccidioides, Histo- GLUCOCORTICOIDS plasma, Candida, Malassezia, Cryptococccus. Poor penetration into CNS, eye, and testes I. Mechanisms of action 2. Topical clotrimazole used for nasal A. Bind intracellular glucorticoid receptor and mod- aspergillosis ify expression profile of genes containing the glu- 3. Fluconazole used for systemic mycoses, corticoid response element (GRE) esp. with ocular, prostate, urinary, or CNS B. Catabolic effects on metabolism involvement 1. Increase in gluconeogenesis C. Side effects and contraindications 2. Decrease in protein synthesis 1. Ketoconazole 3. Increased lipolysis or increased lipogenesis, a. Anorexia and vomiting depending on tissue b. Mild increases in ALT C. Effects on musculoskeletal system: Enhanced c. Inhibits cortisol synthesis. May prevent cor- bone resorption; muscle atrophy tisol stress response D. Effect on CNS: Change in behavior (hyperactivity d. Cytochrome P450 inhibitor. Many potential or somnolence); polyphagia drug interactions E. GI effects: Increased acid secretion and decreased 2. Itraconazole gastric mucosal cell turnover a. Fewer adverse effects than ketoconazole F. Renal effects: Polyuria; increase in potassium and b. Does not inhibit cortisol synthesis calcium excretion c. Cytochrome P450 inhibitor. Many potential G. Effect on cardiovascular system: Promote vaso- drug interactions motor tone; maintain capillary integrity II. Antibiotic antifungals H. Effect on hematopoietic system A. Amphotericin B 1. Thrombocytosis 1. Mechanism of action 2. Neutrophilia, monocytosis a. Selectively binds ergosterol (component of 3. Eosinopenia, lymphopenia fungal cell membrane) 4. Decrease inflammatory mediators (e.g,: prosta- b. Alters fungal membrane permeability (mem- glandins; leukotriens; histamine) brane pore formation) 5. Decrease leukocyte phagocytosis, chemotaxis, c. Binds with less affinity to cholesterol in and antigen processing mammalian cells II. Indications (many) 2. Lipid-complex formulation A. Inflammatory diseases  CHAPTER 9 Pharmacology 105 B. Immune-mediated diseases V. Specific agents C. Atopy and allergic diseases A. COX-1 and COX-2 inhibitors D. Treatment of hypoadrenocorticism 1. Aspirin used to prevent thrombosis; common E. Hypercalcemia GI side effects at antiinflammatory doses F. Maturation of fetus lungs before delivery 2. Phenylbutazone induction a. Used primarily in horses for musculoskeletal III. Side effects (depend on dose, route, and the pain and inflammation duration of the treatment) b. Side effects: Bone marrow suppression, A. Polyuria, polydipsia, polyphagia renal dysfunction (fluid retention to acute B. Lethargy renal failure), gastric ulcers. C. Distended abdomen, thin skin 3. Flunixine: Used in cattle and horses for pain, D. Secondary infections inflammation, and endotoxemia E. Impaired wound healing 4. Piroxicam: Treatment of transitional cell F. GI ulceration carcinoma and other tumors (dogs) G. Diabetes mellitus B. COX 2 preferential: Carprofen, meloxicam, H. Induction of serum alkaline phosphatase (dogs) etodolac I. Pancreatitis C. COX-2 selective: Deracoxib, prevacoxib IV. Contraindications (absolute) D. Dual LOX-5 and COX-2 inhibitor: Tepoxalin A. Systemic fungal infections B. Keratitis, corneal ulcer OPIOID ANALGESICS C. GI ulceration D. Late-stage pregnancy I. Analgesia E. Laminitis in horses (active or potential) A. Analgesia mediated by binding of mu receptors in F. Abrupt withdrawal after chronic treatment the brainstem, and mu, kappa and delta receptors V. Common preparations in the spinal cord A. Short-acting: Hydrocortisone B. Mu ( ) receptors. Localized to pain-regulating B. Intermediate-acting: Prednisone or prednisolone, areas of brain and spinal cord methylprednisolone, triamcinolone 1. Excellent analgesia (dose-dependent) C. Long-acting 2. Sedation and dysphoria 1. Dexamethasone: no mineralocorticoid activity; 3. Respiratory depression, heart rate depression, may be preferable for patients with hyperten- hypothermia, and miosis sion, edema, or ascites 4. GI side effects include nausea, vomiting, and 2. Betamethasone defecation D. Esters formulations C. Kappa ( ) receptors: Brain (cerebral cortex) and 1. Alter solubility and duration of action of spinal cord steroids 1. Mild analgesia 2. Succinate or phosphate esters: Last minutes to 2. Minimal to no sedation hours 3. Mild respiratory depression 3. Acetate: Lasts days to weeks. Diacetate, ace- 4. Rarely causes vomiting tonide, pivalate: Last weeks D. Delta () receptors. Limbic area of CNS and spinal cord 1. Analgesia NONSTEROIDAL 2. Decreased GI motility ANTIINFLAMMATORY DRUGS (NSAIDS) 3. Currently not well understood I. Mechanisms of action: Inhibition of cyclo-oxygenases II. Full opioid agonists 1 or 2 (COX-1, COX-2), leading to inhibition of prosta- A. Morphine glandin synthesis from arachidonic acid 1. Mechanism of action. Full -agonist (but does A. Antiinflammatory interact with all opioid receptors) B. Antipyretic 2. Indications C. Analgesic a. Analgesia for moderate to severe pain; 3 to D. Inhibition of platelet aggregation, via COX-1 4 hours prolonged anesthesia inhibition b. IM use only. Can cause histamine release II. Indications: Musculoskeletal pain, postoperative pain with associated vasodilation (hypotension) and inflammation, fever with IV administration III. Side effects 3. Side effects: Respiratory depression (especially A. Vomiting, diarrhea at high doses). Use with caution in patients B. Gastric ulceration with severe head injuries, metabolic acidosis, C. Impaired renal blood flow or decreased central respiratory drive. Other D. Hemorrhage due to impaired platelet function side effects: Bradycardia, ileus, hyperexcitabil- E. Idiosyncratic liver toxicity ity and agitation (cats) IV. Contraindications: GI ulcers, bleeding disorders, B. Oxymorphone compromised renal function, dehydration, liver 1. Mechanism of action dysfunction. a. Morphine derivative 106 SECTION I GENERAL DISCIPLINES IN VETERINARY MEDICINE b. Full -agonist (but does interact with all C. Side effects include mild respiratory depression. opioid receptors). 10 times as potent as Less likely to cause hyperexcitability and agita- morphine tion in cats. 2. Indications V. Opioid antagonist: Naloxone a. Analgesia for moderate to severe pain; pro- A. Mechanism of action vides 1 to 3 hours of pain relief 1. Pure opioid antagonist b. Specifically approved for dogs and cats 2. Binds opioid receptors but has no effect c. IM and IV administration 3. Competitively displaces opioid agonists from 3. Side effects: As for morphine receptor, reversing the agonists effect C. Fentanyl 4. High affinity for -receptor 1. Mechanism of action 5. Lesser affinity for - and -receptors a. Synthetic opioid B. Indications. Used as a - and -opioid receptor b. Full -agonists antagonist (1) Highly selective for μ receptors 1. Duration relatively short (20 to 30 minutes) (2) 80 times as potent as morphine 2. Reverses CNS and respiratory depression and 2. Indications bradycardia from -agonists a. Analgesia for moderate to severe pain; dura- C. Side effects: Excitement, aggression, hyperalgesia tion of action approximately 20 minutes VI. Other agents: Tramadol b. Most commonly given IV as a constant rate A. Mechanism of action infusion 1. Weak agonistic effect on -opioid receptor c. Transdermal patches are available for lon- 2. Marked effect on the serotonergic system. In- ger term use (up to 3 days) hibits serotonin and norepinephrine reuptake 3. Side effects include respiratory depression and 3. Marked effect on the -2 noradrenergic system bradycardia 4. Active metabolite (O-desmethyltramadol): D. Hydromorphone Has higher potency, and stronger affinity for 1. Mechanism of action the -receptor a. Semisynthetic opioid 5. Minimal effect on respiratory, cardiovascular, b. -agonist and GI systems (1) Relative to morphine 5 times as potent B. Indications: Analgesia (acute and chronic pain) (2) Equal potency to oxymorphone 1. Musculoskeletal pain 2. Indications include sedation, analgesia. Shorter 2. Mixed nociceptive-neuropathic pain duration than oxymorphone 3. Neuropathic pain 3. Side effects: Respiratory depression, bradycar- C. Side effects dia, ileus, or vomiting 1. Use not recommended with selective serotonin III. Partial opioid agonists: Buprenorphine reuptake inhibitors or monoamine oxidase in- A. Mechanism of action hibitors 1. Synthetic opioid 2. Dose reduction recommended in very old pa- 2. Partial -agonists. Binds strongly to μ recep- tients and patients with renal or liver disease tors and may be difficult to displace with an antagonist or another μ agonist ANTICOAGULANTS B. Indications 1. Analgesia (less profound relative to full μ I. Heparin agonists) A. Mechanism of action a. Moderate pain 1. Binds with antithrombin to inhibit thrombin b. Provides analgesia for 4 to 8 hours formation 2. Can act as an opioid antagonist by displacing 2. At higher doses, also blocks fibrin formation pure μ agonists and inactivates factors IX, X, XI, and XII C. Adverse effects B. Indications include thromboembolic disease, dis- 1. Less respiratory depression seminated intravascular coagulopathy (DIC), and 2. More difficult to reverse with naloxone laminitis in horses IV. Opioid agonist-antagonist: Butorphanol C. Side effect is bleeding diathesis. Monitor with A. Mechanism of action APTT; antidote is protamine sulfate 1. Synthetic opioid D. Contraindications: Active bleeding or recent CNS 2. Mixed agonist-antagonist: -receptor agonist; injury or surgery weak -receptor antagonist II. LMWH (low-molecular-weight heparin) B. Indications A. Mechanism of action 1. Analgesia (mild). Duration up to 6 hours in 1. Depolymerized fractionated heparin cats and 4 hours in dogs. Duration of acute 2. Inhibition of secondary hemostasis, as for pain relief is rarely longer than 1 to 2 hours heparin 2. Minimal to no sedation 3. Unlike heparin, affects thrombin itself only at 3. Can reverse effects of -agonists. 1:40 antago- high doses nist potency compared with naloxone B. Indications 4. Antitussive in dogs 1. As for heparin  CHAPTER 9 Pharmacology 107 2. Longer half-life 3. Horses: large and small strongyles, pinworms 3. More predictable pharmacokinetics than un- C. Side effects (uncommon). GI upset in horses fractionated heparin II. Febantel 4. May have lower bleeding risk than unfraction- A. Mechanism of action ated heparin 1. Prodrug for fenbendazole and oxfenbendazole C. Side effects. Does not prolong APTT at standard 2. Binds to microtubules and inhibit cell division doses in nematodes D. Contraindications: Active bleeding or recent CNS 3. Inhibits mitochondrial function in nematodes injury or surgery B. Indications: As for fenbendazole III. Aspirin C. Side effects (uncommon) A. Mechanism of action D. Contraindications: Pregnancy 1. Inhibition of primary hemostasis III. Pyrantel 2. Irreversible COX-1 inhibitor A. Mechanism of action a. Inhibits thromboxane A2 (procoagulant fac- 1. Depolarizating neuromuscular blocking agent tor) synthesis in platelets 2. Increases acetylcholine release and inhibits b. Prevents platelet aggregation cholinesterase c. At low doses, does not adversely affect en- 3. Nicotine-like properties dothelial function B. Indications B. Indications: At low dose: antiinflammatory and 1. Roundworms and hookworms in cats anticoagulant (more efficient on arterial throm- and dogs botic disorders) 2. Large strongyles in horses 1. DIC 3. Not approved for cattle but effective for Hae- 2. Pulmonary arterial disease secondary to heart- monchus, Ostertagia, Cooperia, Trichostrongylus worm infestation C. Side effects: Uncommon 3. Cardiomyopathy in cats IV. Praziquantel 4. Adjunctive treatment in glomerular disease A. Mechanism of action: Increase in cell membrane C. Side effects: Uncommon at low antithrombotic permeability to calcium doses B. Indications: Treatment of tapeworms in cats, dogs, and other species C. Side effects: GI upset; ataxia and pain at injection ANTICONVULSANTS site with injectable form in dogs I. Phenobarbital D. Contraindications: Not for puppies and kittens A. Mechanisms less than 4 weeks old 1. Thought to interact with GABAergic receptors V. Ivermectins 2. Leads to neuronal hyperpolarization A. Mechanism of action B. Indications: Epileptic seizures 1. Semisynthetic analogue of avermectin C. Side effects and contraindications: Hyperexcitabil- 2. Potentiates the action of the inhibitory neu- ity inititally, then sedation; polyuria. polydipsia, rotransmitter GABA polyphagia; induction of serum ALP in dogs; hep- a. Nematodes and arthropods have GABA neu- atotoxicity in some dogs rotransmission in their peripheral nervous II. Bromide system A. Mechanisms: Hyperpolarizes neurons by entry via b. Mammals have GABA neurotransmission chloride channels limited to the CNS, and ivermectins are ex- B. Indications: Epileptic seizures cluded from the CNS in most mammals C. Side effects and contraindications: Hyperexcit- B. Indications ability initially, then sedation; polyuria, polydip- 1. Horses: Large and small stronglyes, pinworms, sia, polyphagia; eosinophilic bronchitis in cats. roundworms, others High chloride intake lowers serum bromide 2. Cattle: Roundworms, lungworms, grubs concentrations 3. Ineffective in liver flukes and tapeworms (do not use GABA neurotransmission) C. Side effects (uncommon) ANTHELMINTHIC AGENTS 1. Local swelling and pruritus after injection I. Fenbendazole 2. Hypersensitivity reactions to dying parasites A. Mechanism of action D. Contraindications: Lactating dairy cows 1. Bind to microtubules and inhibit cell division in nematodes FLEA, HEARTWORM, AND ENDOPARASITE 2. Inhibit mitochondrial function in nematodes PREVENTION B. Indications 1. Dogs and cats: Active against roundworms, I. Preventatives hookworms, whipworms, Giardia spp., and A. Ivermectin (Heartguard and Heartguard Plus) lungworms 1. Mechanism of action: Potentiates the action of 2. Cattle: Haemonchus, Ostertagia, Cooperia, the inhibitory neurotransmitter GABA Trichostrongylus 2. Indications 108 SECTION I GENERAL DISCIPLINES IN VETERINARY MEDICINE a. Efficacy against infective-stage of heart- thromboembolism, and GI upset. Narrow thera- worm larvae in dogs and cats peutic index; more toxic to cats, use in cats b. At higher doses effective as heartworm mi- controversial crofilaricide (not approved for this use) B. Melarsomine (Immiticide) c. No activity against adult heartworms 1. Mechanism of action 3. Side effects a. Organic arsenical a. CNS toxicity: Mydriasis, depression, ataxia, b. Proposed mechanism is arsenical interac- and coma. tions with sulfhydryl groups in parasite en- b. Higher incidence of toxicosis in collies and zymes other herding breeds (shelties, Australian 2. Indications shepherds, and Old English sheepdogs) a. Treatment of adult heartworms and L5 larvae B. Milbemycin oxime (Interceptor) in dogs 1. Mechanism of action: As for ivermectin b. Has replaced thiacetarsamide 2. Indications 3. Side effects include pulmonary thromboembo- a. Effective as heartworm preventative and mi- lism, depression, anorexia, fever, vomiting, and crofilaricide in dogs muscle pain at injection site. Has less hepato- b. Controls infections with hookworms, round- toxicity than thiacetarsamide worms and whipworms in dogs 4. Contraindications c. Available as combination product with a. Dogs with class 4 heartworm disease (heart- lufenuron (Sentinel) worms present in vena cava and right 3. Side effects: Heartworm preventative dose re- atrium) ported to be safe in collies and other herding b. Very toxic to cats and not recommended for breeds this species C. Selamectin (Revolution) 1. Mechanism of action ECTOPARASITICIDES a. As for ivermectin b. Topical administration with systemic ab- I. Agents that kill adult ectoparasites sorption A. Pyrethrins and pyrethroids c. Distributed via the blood to sebaceous 1. Mechanism of action glands of the skin a. Interfere with parasite peripheral nervous 2. Indications system a. Endoparasite prevention or control (1) Block voltage-sensitive sodium channels (1) Prevention of heartworm disease in (2) Increase the release of GABA, an inhibi- dogs and cats tory peripheral neurotransmitter (2) Control of hookworms and roundworms b. Pyrethrins are natural insecticides pro- in cats duced by certain species of the Chrysanthe- b. Topical adulticide for ectoparasitic treat- mum plant ment or control c. Pyrethroids are synthetic pyrethrins (1) Fleas (Ctenocephalides felis) in dogs 2. Indications and cats a. Effective against flies, fleas, lice, and ticks (2) Ticks (Dermacentor variabilis) in dogs b. Rapid knockdown effect with little residual (3) Mange (Sarcoptes scabiei) in dogs activity (4) Ear mites (Otodectes cynotis) in dogs 3. Side effects and cats a. Depression, anorexia, vomiting, hypersaliva- 3. Side effects tion, muscle tremors, ataxia, and dypsnea a. Localized alopecia in cats (site of b. High incidence of toxicity in cats; should administration) not be used in cats b. Rarely (dogs): Diarrhea, vomiting, anorexia, B. Organophosphates (OP) lethargy, salivation, pruritus, urticaria, ery- 1. Mechanism of action thema, muscle tremors, ataxia, and seizures a. Bind and inhibits acetylcholinesterase c. Safe at heartworm-preventative dose in (AchE) via enzyme phosphorylation. AchE avermectin-sensitive breeds (collies and is the enzyme that degrades acetylcholine other herding breeds) (Ach). Results in the accumulation of Ach at II. Heartworm adulticides synapse, producing continuous neuronal A. Thiacetarsamide (no longer used in the stimulation and paralysis of the parasite United States) b. OPs are considered irreversible AchE inhibi- 1. Mechanism of action: Organic arsenical tors. Phosphorylation is only very slowly 2. Indications reversible. Once phosphorylated enzyme a. Heartworm adulticide (Dirofilaria immitis) complex is aged, reactivation of the enzyme in dogs is not possible b. No effect on microfilaria 2. Indications (not commonly used since develop- 3. Side effects: Severe vesicant, nephrotoxicity ment of safer products) and hepatotoxicity possible, pulmonary a. Insecticide (fleas, lice, and flies)  CHAPTER 9 Pharmacology 109 b. Acaricide (mites and ticks) 2. Indications c. Helminthicide a. Topical adulticide 3. Side effects b. Kills fleas but not ticks a. Low margin of safety c. Combination products available: Imidaclo- b. Toxicosis resulting from interference with prid plus permethrin (K9 Advantix) muscarinic and nicotinic neurotransmission 3. Side effects: No toxicity has been reported. Use (1) Muscarinic signs: Miosis, lacrimation, not recommended in sick or pregnant animals salivation, diarrhea, frequent urination, 4. Contraindications. Do not use in animals bradycardia, or hy