Cardiovascular Pharmacology I PDF

Cardiovascular pharmacology I NUNO COELHO, DVM, PHD PHARMACOLOGY AND THERAPEUTICS II MASTER DEGREE – VETERINARY MEDICINE  Summary 1. Introduction ▪ Basic aspects of the cardiac function and the need to modulate it pharmacologically 2. Digitalis 3. Positive inotropes 4. Vasodilator...

Cardiovascular pharmacology I NUNO COELHO, DVM, PHD PHARMACOLOGY AND THERAPEUTICS II MASTER DEGREE – VETERINARY MEDICINE  Summary 1. Introduction ▪ Basic aspects of the cardiac function and the need to modulate it pharmacologically 2. Digitalis 3. Positive inotropes 4. Vasodilators 5. Antihypertensive drugs 6. Antiarrhythmics  Abbreviations ▪ AV: atrioventricular ▪ LA: left atria ▪ Ca: calcium ▪ LV: left ventricle ▪ CHF: congestive heart failure ▪ MMVD: myxomatous vitral valve disease ▪ CNS: central nervous system ▪ PS: parasympathetic nervous system ▪ CO: Cardiac output ▪ RA: right atria ▪ CRI: constant rate infusion ▪ RAAS: renin-angiotensin-aldosterone system ▪ EDV: end diastolic volume ▪ RV: right ventricle ▪ ESV: end systolic volume ▪ S: sympathetic nervous system ▪ HCM: hypertrophic cardiomiopathy ▪ SV: Stroke volume ▪ HR: heart rate ▪ V: ventricle 1) Introduction Another epidemiological data: in a observational study from 3434 horses going to the clinic, 8.3% had cardiac diseases (Leroux, 2013)  1) Introduction American College of Internal Veterinary Medicine - ACVIM purinainstitute.com myxomatous mitral valve disease (MMVD) 1) Introduction: Basic aspects of cardiovascular function Phases of the action potential: (0) rapid depolarization (1) partial repolarization (2) plateau (3) repolarisation (4) resting membrane pot Electrophysiological features of cardiac muscle: pacemaker activity absence of fast Na+ current in SA and AV nodes, where slow inward Ca2+ current initiates action potentials long action potential (‘plateau’) and refractory period influx of Ca2+ during the plateau 1) Introduction: Basic aspects of cardiovascular function Cardiac output (CO): total volume of blood pumped by one ventricle per minute depends on: ▪ Stroke volume (SV) and heart rate (HR) ▪ Neurohormonal control via pressure sensors, CNS, S and PS system and RAAS – important for pharmacology – drugs stimulate or blunt these systems 1) Introduction: Basic aspects of cardiovascular function Preload is the initial stretching of the cardiac myocytes (heart muscle cells) at the end of ventricular filling during diastole influenced by the volume of blood returning to the heart (venous return) Afterload is the pressure that the heart must work against to eject blood during systole 1) Introduction: Basic aspects of cardiovascular function ▪ heart adjusts its pumping activity under normal conditions ▪ e.g. when venous return ↑, the contractile function in the healthy heart ↑, thereby pumping an ↑ volume of blood into the arterial system ▪ heart to autoregulate its pumping capacity in response to end-diastolic filling Frank–Starling law of the heart 1) Introduction: Basic aspects of cardiovascular function 1) Introduction: Basic aspects of cardiovascular function Autonomic nervous system regulates the cardiovascular system, particularly heart (S and PS) modulate heart rate, vascular volume and myocardial contractility change in contractility – inotropy (+ or -) change in heart rate – chronotropy (+ or -) 1) Introduction: Basic aspects of cardiovascular function excitation–contraction coupling in the myocardium ▪ The action potential spreads into the cell via T tubules ▪ voltage‐dependent Ca channels open and extracellular calcium enters the cell and promote the release of more Ca from sarcoplasmic reticulum ▪ Ca: crucial for the muscle contraction 1) Introduction: Basic aspects of cardiovascular function 2) DRUGS THAT AFFECT CARDIAC FUNCTION  2) DRUGS THAT AFFECT CARDIAC FUNCTION Drugs that have a major action on the heart (and vessels) can be divided in groups: 1. Drugs that affect myocardial cells directly, including: a. cardiac glycosides and other inotropic drugs b. autonomic neurotransmitters and related drugs c. antidysrhythmic drugs d. miscellaneous drugs and hormones (e.g. doxorubicin, thyroxine, glucagon) 2. Drugs that affect cardiac function indirectly - these have actions elsewhere in the vascular system: e.g. some drugs that are used to treat heart failure - diuretics and ACEIs 3. Calcium antagonists: affect cardiac function by a direct action on myocardial cells and also indirectly by relaxing vascular smooth muscle 4. Vasodilatory agents, antihypertensive drugs 2) DRUGS THAT AFFECT CARDIAC FUNCTION  3) Inotropic drugs – cardiac glycosides Digitalis and cardiac glycosides Digitalis purpurea Digitalis: derived (dried leaf) from purple foxglove plant (Digitalis purpurea) Digitoxin, digoxin, and gitoxin also can be extracted from a related plant For clinical purposes, only digoxin is relevant digitalis - designate the entire group of drugs, including digoxin glycoside: a compound linked by an oxygen atom to a sugar molecule  3) Inotropic drugs – cardiac glycosides Mechanism of action Inhibition of Na+,K+-ATPase The increased intracellular Na+ reduces Ca2+ extrusion thus increasing intracellular Ca2+ delivery to the contractile proteins is increased positive inotropic effect A decrease in K+ inside can lead to arrhythmogenic properties of digitalis  3) Inotropic drugs – cardiac glycosides Mechanism of action Inhibition of Na+,K+-ATPase at cardiac cells  3) Inotropic drugs – cardiac glycosides Cardiovascular effects Improved myocardial contractility direct effect on contractile strength (positive inotropic action) Other effects: Digitalis also promote neurohormonal normalization Slows HR and Slows AV conduction, reduced rate of conduction and prolongs AV node refractory period treatment of tachyarrhytmias (supraventricular) some diuresis  3) Inotropic drugs – cardiac glycosides Cardiovascular effects Cardiac output - CO Digitalis-increased myocardial contractility augments work capacity of the ventricle, at any given end-diastolic filling pressure Systolic emptying more complete (increased ejection fraction) CO ↑ and the size of the heart is reduced ↑ venous return to the heart - ↑ preload and further enhancing cardiac performance  3) Inotropic drugs – cardiac glycosides Cardiovascular effects Other effects patients with heart failure do not show an increase in the myocardial oxygen consumption because of the slowing of heart rate and the reversal of SNS-derived VC Although the + inotropic effect: HR decrease (chronotropic neg effect) due neuroendocrine effect digitalis’ normalization in the baroreceptor reflex sensitivity ( ↓S in heart failure and vagal stimulation – parasympathomimetic effect) decrease in sinus rate, afterload, and speed of atrioventricular (AV) impulse conduction, thereby reducing cardiac work and MVO2  3) Inotropic drugs – cardiac glycosides Cardiovascular effects Other effects disturbances of rhythm can be seen, especially: block of AV conduction increased ectopic pacemaker activity One of the main drawbacks of glycosides in clinical use is the narrow margin between effectiveness and toxicity enhances automaticity by increasing the slope of phase 4 spontaneous depolarization – cardiac cells reach the threshold for firing action potentials more quickly can lead to arrhytmias!  3) Inotropic drugs – cardiac glycosides PK (digoxin) DOGS: good oral absorption (75-90%), with peak concentrations serum up to 90 min; as for IV administration, the maximal positive inotropic responses to digoxin were obtained within 60 minutes after injection variable half-life: 15 -50 hours – strengthen the need for individual dosage regimens, in particular because of toxicity risk enterohepatic cycle: compounds are excreted by the liver into bile and some parent glycoside and metabolites are subsequently reabsorbed; urinary excretion HORSES: less oral absorption and half-life of 17 hours similar metabolism to dog  3) Inotropic drugs – cardiac glycosides Therapeutic indications Congestive heart failure: indicated in systolic heart failure, but new classes of drugs are taken the place of glycosides atrial fibrillation: digoxin control HR when there is a rapid ventricular response Atrial Fibrillation in Cats  3) Inotropic drugs – cardiac glycosides Toxicity inappetence, depression, mild gastrointestinal: loose stools, vomits, diarrhea, nausea neurological signs Occurrence of ECG abnormalities eventually death Low K+ and high Ca2+ concentration potentiates digitalis arrhythmogenicity and lessens efficacy of the treatment Treatment with toxicity: discontinuing digoxin; serum digoxin concentrations; antidigoxin antibodies (expensive but quick recovery); Antiarrhythmic therapy  3) Inotropic drugs – cardiac glycosides ▪ Therapeutic drug monitoring https://www.genevet.pt/pt/servicos 3) Inotropic drugs – cardiac glycosides Generally, digoxin is initiated at the low end of the dose range, then increased gradually if necessary to achieve the desired therapeutic outcome IV with increased risk for toxicity – PO with good oral absorption - preferable 3) Inotropic drugs – cardiac glycosides Effects: improve myocardial contractility (+ inotropic effect) Slows HR and Slows AV conduction, reduced rate of conduction and prolongs AV node refractory period (- chronotropic effect) promote neurohormonal normalization some diuretic effect  4) Sympathomimetic agents Sympathomimetic Agents: Dobutamine and Dopamine employed dobutamine for the emergency management of heart failure in dogs, less support for dopamine Mechanism of action: improvement in cardiac performance by complexing primarily with myocardial β1 receptors activation of second messengers increase intracellular of calcium → enhance contractility Francis, 2014  4) Sympathomimetic agents Sympathomimetic Agents: Dobutamine and Dopamine Dobutamine: S agonist but without much impact on HR minimally proarrhythmic very short half-life - (1–2 minutes) – effects dissipate quickly, allow quick dose adjustement; short-life requires constant rate infusion (CRI) Dobutamine is beneficial for emergency management of dilated cardiomyopathy (DCM), without atrial fibrillation or other supraventricular tachycardia  4) Sympathomimetic agents Sympathomimetic Agents: Dobutamine and Dopamine Dopamine: although interacting with its receptors (dopaminergic DA1 and DA2), also stimulates cardiac β1 receptors - with the expected positive inotropic, chronotropic, dromotropic, and vasoconstrictive effects because of this “promiscuity” – wide range of cardiovascular effects that vary with dose: lower blood pressure (low dose, DA1 stimulation) increase CO and renal blood flow (intermediate) vasoconstriction, increased systemic resistance and blood pressure (high doses, α1 and α2) Application in vet: management of hypotension during anesthesia and treating noncardiogenic shock  5) Inodilators Inodilators: vasodilatory + positive inotropic properties Cardisure, Fortekor-Plus, Pimocard, Vetmedin, Pimosure Pimobendan: novel agent used in veterinary medicine effective, increased survival, and with a favorable safety profile CLINICAL applications: ▪ clinical management of canine heart failure secondary to either DCM or myxomatous mitral valvular disease (MMVD) ▪ in dogs with DCM and heart failure: significant improvement ▪ clinical trials showed good results for prevention of the onset of signs of congestive heart failure in dogs with cardiac enlargement secondary to preclinical MMVD and in heart failure due to DCM ▪ also with some efficacy in cats (DCM), but less studies ▪ no arrhythmogenic activity  5) Inodilators Pimobendan Mechanism of action It is a phosphodiesterase (PDE) III inhibitor Inotropic effects: mediated via sensitization of the myocardial contractile apparatus to intracellular calcium and by phosphodiesterase (PDE) III inhibition ▪ Calcium sensitization allows the enhancement of the interaction between calcium and troponin C for a positive inotropic effect without an increase in myocardial oxygen demand. Vasodilation: mediated by PDE III and V inhibition (these PDE are also located in vascular smooth muscle) → vaso- and venodilation  5) Inodilators Pimobendan Saengklub, 2022 PK and formulations ▪ quick oral absorption - peak plasma levels within an hour ▪ oral bioavailability of 60-70%, but reduced with food ▪ administer at least 1h after feeding until steady state is reached ▪ water insoluble, highly protein bound (90%–95%), excreted into bile, and eliminated in the feces ▪ metabolized (demethylated) in the liver; major metabolite (desmethylpimobendan) is more potent inhibitor of PDE III (vasodilation) than pimobendan and has a slightly longer half-life well tolerated in dogs ▪ formulated in gelatin capsules or chewable tablets (1.25, 2.5, 5 or 10 mg)  6) Other inotropic agents Inotropic Agents: Inamrinone and Milrinone ▪ Inamrinone (formerly amrinone) and milrinone are bipyridine derivatives commonly referred to as nonglycoside, noncatecholamine inotropic drugs ▪ apart from inotropic action, also with peripheral vasodilator effect ▪ “inodilator”, alternatives to digoxin in congestive heart failure ▪ not much used clinically  6) Other inotropic agents Inotropic Agents: Inamrinone and Milrinone Mechanism of action Milrinone is a potent selective inhibitor of phosphodiesterase 3 (PDE III), one of the enzymes which breaks down cAMP The inotropic effects (and all the adverse effects) stem from the resulting increase in cAMP 7) Drugs that inhibit the RAAS Angiotensin converting enzyme inhibitors - ACEi Angiotensin receptor antagonists, also known as angiotensin receptor blockers (ARBs)  7.1) ACEi ACEi - Angiotensin-Converting Enzyme Inhibitors Almeida & Coimbra, 2019 0 4 2 3 1 5 Renin-angiotensin-aldosterone system (RAAS) 7.1) ACEi 1. Reduced renal perfusion with heart failure 2. renin release from JXG apparatus 3. Formation of AngII (potent vasoconstrictor) 4. With chronicity, these hormones become deleterious by ACEi 5. causing vasoconstriction, pathological remodeling of the myocardium and vessels, sodium and fluid retention, potassium wasting, and baroreceptor dysfunction  7.1) ACEi ACEi - Angiotensin-Converting Enzyme Inhibitors The first ACEI to be developed was captopril commonly used in veterinary – enalapril and benazepril (+) there are others: captopril, lisinopril, imidapril, alacepril, and ramipril Blockade of angiotensin II and aldosterone production blunts the negative effect of pathological remodeling of the heart, vasculature, and kidney in states of pathological RAAS (over)activation represent a cornerstone in the chronic management of heart failure in cats the efficacy is not as relevant chronic kidney disease, protein-losing nephropathy 7.1) ACEi ACVIM recommends ACEi in these stages of cardiac disease in dogs (MMVD)  7.1) ACEi ACEi - Angiotensin-Converting Enzyme Inhibitors Mechanism of action The ACEIs commonly used in veterinary medicine, with the exception of captopril and lisinopril, are administered PO as prodrugs and converted to their active form in the liver (enalaprilat and benazeprilat) Inhibits angiotensin-converting enzyme (ACE), reducing angiotensin II and aldosterone secretion – quick, intense and long-lasting effect Result: increased salt and water excretion, decreasing plasma volume and cardiac load 7.1) ACEi Main effects of ACEi Inhibition of angII production also increases bradikynin mixed VD – arterial and venous ↓ plasmatic volume ↓ sympathetic activation Stabilization of the glomerular basal membrane - prevent proteinuria ↓ glomerular hypertension in CKD patients Inhibition of growth factoers in the role of glomerular hypertrophy and sclerosis ↓ preload and afterload of the heart ↓ renal, cardiac and vascular deleterious effects of aldosterone and angiotensin II  7.1) ACEi PK aspects benazepril excretion of the active metabolite by enterohepatic and renal pathway – can be given to animals with kidney disease other ACEi are eliminated mostly by the kidney (captopril, enalapril) pharmacological activity last between 12-72h (benazepril) Adverse effects ▪ symptomatic hypotension (VD effect) ▪ reducing renal perfusion pressure and GFR (renal impairment, azotemia) – but impact seems minimal ▪ Cough and angioedema may occur, but not common in animals ▪ It is well accepted that ACEI administered chronically to animals are beneficial, even with renal failure  7.1) ACEi Enalapril (Enacard); PO (1, 2.5 mg, 5, 10 or 20 mg tablets) Benazepril – oral tablets; (Benazecare Flavour, Benefortin, Cardalis, Fortekor, Fortekor-Plus, Kelapril, Nelio, Prilben, Vetpril  7) ARBs Group of drugs that function as an angiotensin II receptor blocker (ARBs) Telmisartan (Semintra and Telmitraxx – vet; micardis – human) Mechanism of action directly blocks the receptor, rather than inhibits synthesis of angiotensin II (as ACEi) high affinity and selectivity for the angiotensin II subtype 1 (AT-1) receptor PK half-life of 5h (dogs) and 8h (cats) oral absorption is lower with feeding 7) ARBs Clinical indications systemic hypertension in cats and proteinuria caused by CKD more effective than ACEi 1.5 mg/kg PO q12h initially for the first 14 days. Then, 2 mg/kg PO q24h In dogs – less studies, but may be used for the same uses as in cats, when other agents such as ACEi are ineffective or not tolerated Form available in vet: 4 mg/ml oral solution Adverse events: some transient hypotension may occur  7.2) Mineralocorticoid Receptor Blockers Spironolactone: synthetic 17-lactone drug that is a competitive aldosterone receptor antagonist (mineralocorticoid receptor blocker – MRB) leads to increase in urinary Na+ and H2O excretion and a decrease in K+ excretion The antagonism of aldosterone is also important, because of the role of this substance in pathological cardiac remodeling (inflammation, hypertrophy, fibrosis) primary rationale for adding spironolactone as adjunctive therapy (e.g. added to ACEI) for heart failure is aldosterone blockade  7.2) Mineralocorticoid Receptor Blockers Spironolactone In the dog, spironolactone is relatively quickly absorbed through the gastrointestinal tract into the plasma and is then converted to several active metabolites bioavailability in the dog is highest when given with food (80–90%) Clinical use: adjuvant therapy for dogs with stage D and C heart failure, in particular secondary to MMVD (virtually in all instances in which ACEI are used – adjuvant!  8) Other vasodilators Vasodilators 1. venous dilators or venodilators – reducing preload; nitroglycerin as a paradigmatic example 2. arteriolar dilators or arteriodilators – reducing afterload; hydralazine and amlodipine as examples 3. mixed” or “balanced” vasodilators: dilate both arterioles and veins – examples: ACEIs, prazosin, pimobendan, and nitroprusside Rationale to use these drugs in heart failure: decreasing the workload of the heart is better for the patient than administering a positive inotropic agent with toxic potential (i.e., digitalis) and which typically increases MVO2 8) vasodilators  8) Other vasodilators Prazosin: is an α1-adrenergic selective blocking agent ▪ May be useful to treat renal hypertension, vesicourethral reflex dyssynergia in dogs, but not very used Hydralazine Hydrochloride: arteriolar dilator ▪ decrease peripheral and pulmonary vascular resistance, and lowers impedance to left ventricular ejection; SV and CO ↑ proportionately → hemodynamic improvement ▪ Clinical indication: management of congestive heart failure, secondary to MMVD, but few data ▪ dogs: initial oral administration of 1 mg/kg, BID ▪ absorbed rapidly after PO, its onset of action is within 1 hour, and peak response at 3–5 hours ▪ Tachycardia (more frequent) and hypotension may occur as adverse effects  8) Other vasodilators Calcium channel blockers heterogenous group of drugs that can be classified into two groups A) dihydropyridine group: amlodipine, nifedipine greater vascular selectivity B) nondihydropyridine: diltiazem, verapamil act on cardiac electric conduction greater selectivity for nodal and myocardial tissues Mechanism: selectively inhibit the L-type Ca++ channel – preventing its opening in smooth muscle and/or the myocardium 8) Other vasodilators  8) Other vasodilators Main effects of carcium channel blockers Vasodilation of systemic arterioles ​(due ↓ peripheral vascular resistance) Calcium channel blockers ↓ circulating volume Coronary vasodilation Pharmacological effects ↓ blood pressure Negative chronotropic, dromotropic, and inotropic effects (also antiarrhtymic) Calcium channel blocking drugs induce negative inotropic effects: smooth muscle relaxation and a vasodilatory response peripheral vasodilation and ↓ in peripheral vascular resistance, ↓ impedance to left ventricular ejection ↓ ventricular wall tension (afterload) in ejection  8) Other vasodilators Calcium channel blockers Clinical use Verapamil and Diltiazem more for tachyarrhythmias ▪ treatment to control HR in cats with HCM ▪ dog with atrial fibrillation amlodipine: ANTIHypertensive effect ▪ management of systemic hypertension in cats (less in dogs) – 0.1-0.25 mg/kg, PO, q24h (increase up to 0,75 mg/kg with refractory Tx) - tablets ▪ peripheral and coronary VD, less effect in cardiac function ▪ hypotensive effect seen after 4-5 days Adverse effects: negative inotropic effect can reduce CO and hypotension  8) Other vasodilators Nitrovasodilators: Nitroglycerin, Isosorbide Dinitrate, Nitroprusside The organic nitrates exert their effect by acting as an exogenous source source for NO (endogenous vasodilator) Mechanism of action: activate the enzyme guanylate cyclase increase in intracellular cyclic-GMP - acts to inhibit contraction of vascular smooth muscle Nitrates may also stimulate synthesis of the vasodilator PGI2 and PGE Relaxation in arteries and veins – but are more used as preload reducers Hypotension as side effect  8) Other vasodilators Nitrovasodilators PK: very quick metabolization – half times of minutes (1-3) ▪ have significant first-pass effects, and metabolites much less potent → topically , sublingually, or intravenously administration to avoid first-pass metabolism by the liver ▪ topical ointment of 2% for dogs, creams, sublingual tablets, lingual spray or buccal tablet ▪ nitroglycerin is usually applied topically; sodium nitroprusside: potent vasodilator, administered as CRI because of short life ▪ use in vet is limited: dosage forms can be inconvenient and the duration is brief; but may be helpful for VD and acute treatment of pulmonary edema associated with congestive heart failure 8) Other vasodilators ▪ Sildenafil (Viagra) - orally active PDE V inhibitor: prevent degradation of cGMP – relaxation of smooth muscle in pulmonary vasculature and systemic vessels; treatment of pulmonary hypertension in dogs (2 mg/kg sildenafil every 8–24 hours); few data Carvedilol - nonselective β1 and β2-receptor and α1-receptor antagonist ▪ reduce myocardial workload by lowering heart rate and peripheral vascular resistance ▪ treat hypertension and heart failure in humans; in dogs very few studies are available, although suggesting a potential role in heart failure management 9) Antihypertensive therapy Ramirez, 2017 systolic arterial pressure diastolic arterial pressure  9) Antihypertensive therapy Elliot, 2020 No matter the cause and mechanisms involved, hypertension always cause tissue/organ damage target organ damage kidney, heart, central nervous system, arteries and eyes are the most affected organs those effects manifest more in the capillary blood flow Ramirez, 2017  9) Antihypertensive therapy – causes of hypertension Chronic kidney disease Chronic kidney disease Cushing Disease (hyperadrenocorticism Hyperthyroidism Diabetes mellitus Diabetes mellitus Chronic heart failure Chronic heart failure Cardiac hypertrophy Cardiac hypertrophy Pheochromocytoma Pheochromocytoma Conditions with tachycardia (sympathetic stimulus): anemia, fever Hyperaldosteronism Vascular lesions Conditions with tachycardia (sympathetic stimulus): anemia, fever Hyperviscosity in the blood Vascular lesions Intracranial lesions Hyperviscosity in the blood Obesity Intracranial lesions Obesity Ramirez, 2017  9) Antihypertensive therapy Elliot, 2020  9) Antihypertensive The main goal: attain a progressive and gradual reduction in blood pressure until the normal values (or the closest normal values possible) Ramirez, 2017 Mechanism of action of antihypertensive drugs is based on 3 ways: 1. Change the cardiac output (not the most convenient) 2. Control the volume of blood circulating (not the first choice) – e.g diuretics 3. Vasodilation – the best options (1st choice to start reducing BP)  9) Antihypertensive – α and β blockers α – prazosine, doxazosine, terazosine, tamsulosine, urapidilo few studies and few use; may lead to hypotension prazosine is the 1st option for HTN due pheochromocitoma β – atenolol, propanolol more used than α blockers Sympathethic blocking and reduce RAAS activation Precautions: diabetes, obesity, respiratory diseases (as asthma) Drugs of election for HTN associated to hyperthyroidism, pheochromocytoma, other neoplases Don’t stop abruptly – reduce daily doses for 10-15 days mixed (non selectives) – labetalol and carvedilol cardiac effect + arterial VD (due to α block)  9) Antihypertensive Elliot, 2020 Elliot, 2020 ACVIM consensus statement: Guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats; 2018 Elliot, 2020 Thank you! Questions? References RIVIERE, J. E., & PAPICH, M. G. (EDS.). (2018). VETERINARY PHARMACOLOGY AND THERAPEUTICS. JOHN WILEY & SONS. RITTER, J. M., FLOWER, R., HENDERSON, G., LOKE, Y. K., MACEWAN, D., & RANG, H. P. (2020).RANG AND DALE'S PHARMACOLOGY. PHILADELPHIA, PA: ELSEVIER. LÜLLMANN, H., MOHR, K., HEIN, L., & BIEGER, D. (2018). COLOR ATLAS OF PHARMACOLOGY. NEW YORK: THIEMETILLEMENT, J. P. ALLERTON, F. (2020). BSAVA: SMALL ANIMAL FORMULARY (ED. 10). BRITISH SMALL ANIMAL VETERINARY ASSOCIATION ELLIOTT, J., SYME, H. M., & JEPSON, R. E. (EDS.). (2020). HYPERTENSION IN THE DOG AND CAT (P. 20220004167). SPRINGER INTERNATIONAL PUBLISHING. RAMÍREZ, E. Y. (2017). MANUAL CLÍNICO DE PRESIÓN SANGUÍNEA EN PERROS Y GATOS. SERVET. DERANGEDPHYSIOLOGY.COM