Cardiovascular DrugsCardiovascular Drugs(Veterinary Pharmacology)(Veterinary Pharmacology)

dr. Dian Nugrahenny, M.Biomed.Dr. drg. Nur Permatasari, MS.

© 2004 by Thomson Delmar Learning, a part of the Thomson Corporation.

Basic Anatomy and PhysiologyBasic Anatomy and Physiology

Functions of cardiovascular system: Delivery of oxygen, nutrients, and hormones to the various parts of the body Transports waste products to the appropriate waste removal system

Component of Cardiovascular Component of Cardiovascular SystemSystem Cardiac Blood vessels Blood

Guyton Textbook of Medical Physiology, 11th ed.

Guyton Textbook of Medical Physiology, 11th ed.

Basic Anatomy and PhysiologyBasic Anatomy and Physiology

Cardiac Cardiac sympathetic sympathetic and and parasympathetic parasympathetic nervesnerves

Guyton Textbook of Medical Physiology, 11th ed.

Possible mechanisms for influencing Possible mechanisms for influencing heart functionheart function

Lüllmann et al. 2000. Color Atlas of Pharmacology, 2nd ed. Thieme.

Processes in Processes in myocardial myocardial contraction contraction and and relaxationrelaxation

Lüllmann et al. 2000. Color Atlas of Pharmacology, 2nd ed. Thieme.

Cardiovascular DiseasesCardiovascular Diseases

Hypertension

Arrhythmia

Cardiomyopathy

Heart failure

Thromboembolism

Congestive Heart FailureCongestive Heart Failure

Right Heart FailurePredominant: Sign:

venous congestionSubcutaneous

edemaAbdominal effusion

(ascites)HepatomegalySplenomegaly

Left Heart FailurePredominant: SymptomDyspnea, orthopnea, cough (pulmonary edema)

Inadequate tissue perfusion from a failing pump, volume overload Major causes: hypertension, myocardial infarction

Drugs for Heart Failure

3D:VasoDilators:

Venodilators Arteriolar dilators

DiureticsDigitalis

VasodilatorsVasodilatorsVenodilators: Reduces preload by trapping blood in the venous circulationArteriolar dilators: Reduces afterload by reducing arterial resistance

Potensial sideeffect: hypotension

Lüllmann et al. 2000. Color Atlas of Pharmacology, 2nd ed. Thieme.

NitratesNitrates• Drugs: nitroglycerin,

ISDN, ISMN.• As NO donors.

• The effect is more pronounced in venous than in arterial beds.

CaCa2+2+-Channel -Channel Blocker (CCB)Blocker (CCB)

Inhibition of cardiac functions by VERAPAMIL

Inhibit the influx of Ca2+ ions without affecting inward Na+ or outward K+ currents to a significant degree.

Nifedipine

Verapamil used as an antiarrhythmic drug

Renin-Angiotensin-Aldosterone System (RAAS)

ACE Inhibitor:

enalapril, benazapril, imidapril

Action of Angiotensin IIAction of Angiotensin II

Adrenal cortexreabsorption

Other VasodilatorsOther Vasodilators Hydralazine:

Dilate arterioles Treats hypertension Less postural hypotension

Minoxidil: Dilate arterioles For severe hypertension

Diazoxide: Given i.v. causes prominent arteriolar dilation For hypertensive crises Can be used in the management of insulin-secreting pancreatic tumors.

Nitroprusside sodium: Dilate venous and arterioles Given i.v. for hypertensive crises

Diuretics Drugs with a direct renal action. Augment urine excretion (diuresis) by inhibiting the

reabsorption of NaCl and water.

Indications:

1. Mobilization of edemas: increase renal excretion of Na+ and H2O.

2. Antihypertensive therapy: decrease peripheral resistance.

3. Therapy of congestive heart failure: decrease peripheral resistance, cure symptoms of venous congestion.

Adverse effectsAdverse effects of diuretics of diuretics

Massive use of diuretics entails a hazard of adverse effects: The decrease in blood volume can lead to hypotension and collapse; Blood viscosity rises due to the increase in erythro- and thrombocyte concentration, bringing an increased risk of intravascular coagulation or thrombosis.

Action of diuretics1. Thiazides (e.g. HCT): act in the

intermediate segment of distal tubules.2. Loop diuretics (e.g. furosemide): act in the

thick portion of the ascending limb of Henle’s loop.

3. K+-sparing diuretics (e.g. spironolactone): an aldosterone antagonist, act in the distal portion of the distal tubule and the proximal part of the collecting ducts.

In severe cases of myocardial insufficiency, digitalis may be added to augment cardiac force (positive inotrope) and to relieve the symptoms of insufficiency.

Digoxin is a weak positive inotrope. Very narrow therapeutic index. Very long half-life, about 30 hours in dog and 20 hours in

cat. Digoxin has many drug interactions: diuretics,verapamil,

amiodarone, etc.

Digitalis, Digitalis, cardiaccardiac glycosidesglycosides

Digitalis inhibits Na+/K+-ATPases activity. NaNa+ utilizes Na utilizes Na+/Ca/Ca2+ exchange exchange mechanism to enable Namechanism to enable Na+ to exit the cell, in return Ca to exit the cell, in return Ca 2+ enters the cells.enters the cells.The increase of cytosolic CaThe increase of cytosolic Ca2+ promotes a positive inotropic response. promotes a positive inotropic response.

Adverse effectsAdverse effects of digitalis of digitalis

Dysrhythmias Toxicity – very narrow therapeutic index – hypokalemia makes

it easier for toxicity to occur Nausea, vomiting Disturbances of color vision Fatigue

Therapy of intoxication of digitalisTherapy of intoxication of digitalis

Administration of K+, which reduces binding of digoxin, but may impair AV-conduction.

Administration of antiarrhythmics, such as phenytoin or lidocaine.

Oral administration of colestyramine for binding and preventing absorption of digitoxin present in the intestines (enterohepatic cycle).

Injection of antibody fragments (Fab) that bind and inactivate digitoxin and digoxin.

Beta-blockerBeta-blockerBy blocking cardiac β-receptors, cardiac work can no longer be augmented above basal levels.

This effect is utilized prophylactically in angina pectoris to prevent myocardial stress that could trigger an ischemic attack.

β-Blockers also serve to lower cardiac rate.

Agonist Antagonist

Cardiac Arrhythmias

Autonomic nervous system disorders

Altered ionic permeability of cardiac membranes

Factors: trauma; hypoxia; infection; metabolic disease;

drugs and toxins

Intrinsic cardiovascular disease

Autonomic nervous system disorders

Altered ionic permeability of cardiac membranes

Factors: trauma; hypoxia; infection; metabolic disease;

drugs and toxins

Intrinsic cardiovascular disease

Cardiac impulse generation and Cardiac impulse generation and conductionconduction

AARDs: General Mechanisms of Action

Change gating properties of cardiac ion channels

(Na+, Ca2+, K+) directly

Change neuromodulatory control of cardiac ion

channel opening/closing

Change gating properties of cardiac ion channels

(Na+, Ca2+, K+) directly

Change neuromodulatory control of cardiac ion

channel opening/closing

Classification of Classification of AARDsAARDs

a) Variables for normal tissue models in ventricular tissue. b) Variables for SA and AV nodal tissue only. c) Also has type II β-blocking actions. d) Classification controversial. e) Not clinically manifest. f) Also has sodium, calcium, and β-blocking actions.

Hemostasis and Thrombosis

C. SECONDARY HEMOSTASIS

lateletsadhesion

ADP, adenosine diphosphate; t-PA, tissue type plasminogen activator

Hemostasis and Thrombosis

Parenteral anticoagulantsParenteral anticoagulants

Heparin Administered by injectionHelps inactivate thrombin, factor Xa and others*Prophylaxis of venous thrombosisHalf-life is short

Therapeutic usesTherapeutic uses

Pregnancy – if needed Open heart surgery Deep Vein Thrombosis Acute MI

Adverse reactionsAdverse reactions

Bleeding Thrombocytopenia – heparin induced Hypersensitivity Must monitor aPTT (activated partial thromboplastin

time)

Oral anticoagulantsOral anticoagulants

Warfarin

Act as “false” vitamin K and prevent regeneration of active vitamin K from vitamin K epoxide, hence the synthesis of vitamin K-dependent clotting factors.

Vitamin K promotes activation of factors II, VII, IX, and X.

Peak effects take several days.

Therapeutic usesTherapeutic uses

Long-term prophylaxis of thrombosis Must monitor PT (prothrombin time)/INR (international

normalized ratio, contains a correction factor for PT)

Adverse reactionsAdverse reactions

Warfarin has many drug interactions Hemorrhage Vitamin K can be given in case of overdose

Antiplatelet drugsAntiplatelet drugs

AspirinPrevention of thrombosis in arteriesSuppresses platelet aggregation due to inhibition of thromboxan (TXA2) synthesisIndications: prophylaxis of MI, prevent reinfarction in patients with acute MI, prevent strokeLow dose - no greater than 325 mg/dayAdverse effects: GI bleeding, bronchoconstriction

Hypertension

Primary (essential): 90% Secondary Virtually no symptoms Treatment is usually life-long Consequences of hypertension: heart disease, kidney

disease, blindness, stroke

Pharmacologic TherapyPharmacologic Therapy

Sites of action:1.Brainstem2.Sympathetic Ganglia – used for emergencies3.Terminal of adrenergic nerves

Beta 1 receptors on the heart

Alpha 1 – adrenergic receptors on blood vessels

4. Vascular smooth muscle

5. Renal tubules Angiotensin-

converting enzyme Angiotensin II

receptors6. Calcium antagonist

Initial drug therapy choicesInitial drug therapy choices

DiPiro et al. 2005. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. The McGraw-Hill Companies, Inc.

DiPiro et al. 2005. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. The McGraw-Hill Companies, Inc.

Compelling indicationsCompelling indications

Treatment of Chronic Hypertension in Treatment of Chronic Hypertension in PregnancyPregnancy

DiPiro et al. 2005. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. The McGraw-Hill Companies, Inc.

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