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Pharmacology by Dr. Getachew Tadesse,DVM,MSC,PhD@AAU
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Pharmacology by Dr. Getachew Tadesse,DVM,MSC,PhD@AAU

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Pharmacology by Dr. Getachew Tadesse,DVM,MSC,PhD@AAU Pharmacology by Dr. Getachew Tadesse,DVM,MSC,PhD@AAU Presentation Transcript

  • The Heart
  • Rhythm of the Heart•contract sequentially (atria,then ventricles) and insynchronicity•relaxation between contractionsto allow refilling of chambers•controlled electrically
  • Cardiac cycle Primarily accomplished by sinoatrial node (SA)When stimulated, SA signals atrial contractile fibers, followed by atrial depolarization and contraction Depolarization picked up by atrioventricular node (AV node)  depolarizes ventricles  blood discharged to pulmonary artery and dorsal aorta and to the rest of body
  • Regulation of Blood PressureArterial blood pressure due to combination of cardiacoutput (CO) and total peripheral resistance (TPR)CO – regulated by heart rate and stroke volume (CO =HR x SV)TPR function of Viscosity of blood (hematocrit) Length of blood vessels Blood vessel luminal diameter (especially precapillary arterioles)
  • Heart rate Function of sympathetic, vagal nervous activity Neuro-hormonal substances 1° angiotensin II 2º vasopression (anti-diuretic hormone = ADH)Stroke volume Function of Venous return (function of venous tone [contractile state] and circulating blood (vascular) volume) Venous tone is a function of sympathetic activity (α1, α2 receptors) Vascular volume depends on Intake of fluids (thirst) Output of fluids (urine, sweat, etc) Distribution of fluids Myocardial contractility (MC proportional to sympathetic tone [β1 receptors])
  • Cardiovascular abnormalities Could arise due to •Failure in cardiac pumping ability • Problems associated with the Integrity of vasculature •Disturbance in blood volume/composition
  • Cardiovascular PathologiesCould be anatomic or physiologicValvular DiseasesInadequate closure of valves leads to regurgitation.•mitral regurgitation•tricuspid regurgitation•aortic regurgitation•Pulmonic regurgitation
  • Stenosis inadequate opening of valves•Pulmonic•aortic stenosis•mitral stenosis• subaortic stenosis•Tricuspid
  • Cardiac Shunts•Atrial septal defect•Ventricular septal defect•Patent ductus arteriosus•Teratology of fallot
  • Myocardial Diseasereduced systolic function- Impaired force ofcontractionreduced diastolic function -Impaired ventricularrelaxation
  • Cardiac arrhythmiaRefer to a heart beating too fast, too slowly,or too irregularly to sustain an acceptablecardiac output. It could be due to Atrialfibrillation, Ventricular prematuredepolarazation, Ventricular fibrillationSick sinus syndrome, heart block
  • Vascular DiseaseHypertension Interference to blood flowHypotension Relaxation of the blood vessels and reduced blood flow
  • Major Cardiovascular Pathologiespharmacological interventionsHeart failureHypertension/HypotensionArrhythmia
  • I. Positive Inotropesincrease the strength of cardiac muscle contraction by increasingthe quantity of intracellular calcium for binding by muscleproteins.Intracellular calcium can be increased•by altering the Na+/Ca2+ exchange pump• by increasing production of cyclic adenosine monophosphate(cAMP) via stimulation of adenylate cyclase• by decreasing degradation of cAMP via inhibition ofphosphodiesterases.•Provision of calcium
  • A. Cardiac glycosidesDigitalis -Digoxin and DigitoxinMechanism of action (MOA)inhibits the membrane-bound Na+/K+ -ATPase pumpresulting in•an increase of Na+ in the cell•augmentation of the exchange of Na+ for Ca2+=increased calcium influx. =increased release of Ca2+ from thesarcoplasmic reticulum =increased contractility of the cardiac muscle.
  • Cardiac glycosides cont…•can directly slow sinus nodal activity due to increased sensitivity to acetylcholine.•has a negative chronotropic effect due to decreased conductionvelocity in the atrioventricular (AV) node.•Digitalis improve vascular baroreceptor responsiveness, therebyminimizing sympathetic activation in heart failure states.
  • ToxicityToxic effects with digitalis glycosides are frequent andcan be lethal.•cardiac arrhythmias sinus bradycardia Atrioventricular block ventricular arrhythmias•hypokalemia•diarrhea, anorexia, nausea and vomiting• malaise and drowsiness
  • B. Beta adrenergic agonistsactivate β-receptors with subsequent stimulation ofadenylate cyclase and increased cAMP. Dopamine•Has a D and β activity.•stimulates renal dopaminergic receptors which causesincreased renal blood flow and diuresis.•stimulates the release of norepinephrine.•not effectively absorbed if given PO.• rapidly metabolized by the body and has a half-life of <2min.•Cardiac arrhythmias, hypertension, CNS stimulation
  • Dobutamine•similar to dopamine•does not cause release of norepinephrine andtherefore has minimal effects other than β1 -activity.•more effective than dopamine effects•does not dilate the renal vascular bed.•not effective if given PO and has a plasma half-life of about 2 min.•cardiac arrhythmia, CNS stimulation
  • Epinephrine, Isoproterenol•Non selective adrenergic agonists•MOA- adrenergic agonists, increased cAMP,•Indication -cardiac arrest, shock, short term therapy•ADR – tachycardia-increase in oxygen need may be detrimental to the failing heart, hypertension CNS effects
  • C. Phosphodiesterase (PDE) inhibitors•Theophylline• Inamrinone, milirinoneMOA-block the breakdown of cAMP and therefore increase intracellular cAMP concentrations; an increase in myocardial contractility.Indications-heart failureADR-tachycardia, CNS stimulation
  • D. Calcium preparation•Is a positive inotrope•Indication –hypocalcemia•given as a slow IV injection or Infusion.•ADR- hypercalcemia, cardiac rigor andstandstill at high doses.
  • II. Negative inotropesA. Sodium channel blockersLidocaine, procainamide,tocainide, flecainide, mexiletene,Quinidine,LidocaineMOA- block sodium channel, slow phase 0 depolirization and increases the duration of the action potentialIndication-ventricular tachycardiaAdverse effect – bradycardia, hypotension,CNS depression
  • QuinidineMOA-blocks some sodium channels, slows phase 0 depolarization and increases the duration of the action potential; has anti vagal effectsIndications- supraventricular and ventriculartachycardiaADR-sinus bradycardia, Hypotension, increasedimpulse conduction and cardioacceleration
  • B. Potassium channel blockersAmiodaroneMOA-prolongs the duration of the action potential by slowing repoliraztionIndications-suupraventricular and ventriculartachyarrhythmiasADR-hypokalemia, bradycardia, hypotension
  • C. Calcium-channel blockers•Nifedipine, isradipine, etc…Verapamil, diltiazem•MOA-Block entry of calcium into the cell•Indications-hypertrophic cardiomyopathy,supraventricular tachycardia.•ADR-bradycardia, hypotension
  • D. Beta receptor blocking agentsPropanolol,timolol,nadolol,oxprenolol block beta 1 and 2Atenolol, metoprolol -beta 1MOA-bind to beta receptors and prevent theiractivation by epinephrine and nor epinephrineIndications-supraventricular tachycardia,hypertrophic cardiomyopathyAdverse effects-bradycardia, hypotension,hypoglycemia,bronchospasm by the non specificblockers
  • III- Vasoactive Drugs•afterload reducers Afterload is reduced by dilation of arterioles (ie, resistance vessels)•preload reducers preload is reduced by dilation ofveins (ie, capacitance vessels).
  • A. Hydralazine•MOA-relaxes arteriolar smooth muscle probably by inhibiting calcium fluxes into the cell; decrease in peripheral vascular resistance without a decrease in myocardialcontractility;•Indications-used to reduce afterload•ADR-Hypotension may develop; reflex tachycardia; increased myocardial oxygen demand, Myocardial infarction
  • B. Nitrates,nitrites,nitrososNitroglycerin,nitroprusside,sodium nitrate,glyceryl trinitrate, isosorbide dinitrateMOA- NO production; increases cGMP activity;smooth muscle relaxation and reduction ofpreload and after loadIndications-hypertension, heart failureADR-hypotension, reflex tachycardia
  • C. Calcium-channel blockers•Nifedipine, amlodipine etc…Verapamil, diltiazem•MOA-Block entry of calcium into the cell•Indications- hypertension,heartfailure•ADR-bradycardia, hypotension•Amlodipine no effect on cardiac cells
  • D. α1 -adrenergic receptor blocker•Prazosin, doxazosin= alpha 1•Phentolamine, phenoxybenzamine-alpha 1and 2•Tolazoline, yohimbine –allpha 2•Prazosin•is an α1 -adrenergic receptor blocker; block the actions ofepinephrine and norepinephrine; a preload and afterloadreducer.•Indication-hypertension, cardiac failure•ADR- hypotension, tachycardia
  • E. Angiotensin Converting Enzyme Inhibitors(ACE-I) Enalapril , Captopril, Benazepril etc…MOA- prevention of the conversion of Angiotensin I (AT I) to Angiotensin II (AT II, which is a vasoconstrictor) and result in Vasodilation (↓ afterload, ↓ BP)Indication-hypertension, cardiac failureADR- Hypotension, tachycardia, renal dysfunction, GIT disturbance, ↑ K+, Angioedema, ↑ BUN
  • F. Angiotensin Receptor Blockers (ARB)Candesartan, Irbesartan, LosartanMOA -blocks Angtiotensin II, a vasoconstrictor, at the receptor sites, effect similar to ACE I; Vasodilation (↓ afterload, ↓ BP) Indication-hypertension, cardiac failureADR- Hypotension, tachycardia, renal dysfunction, GIT disturbance, ↑ K+, Angioedema, ↑ BUN,
  • IV. VasoconstrictersEpinephrine, norepinephrine, phenylphrine,ephederine, amphetamineMOA-stimulation of alpha adrenergic receptorsIndication-hypotension / shockADR- CNS stimulation, tachyarrhythmia
  • V. HemostaticsAre agents that enhance blood clottingA.Topical •Lyophilized concentrates- thrombin, collagen •Epinephrine, norepinephrine •Formalin 1% •Astringents (Silver nitrate, Ferric chloride, tannic acid
  • B. SystemicVitamin KIt is a systemic hemostatMOA-enhances the synthesis of clotting factors( VII, II, IX, X)Indications-vitamin k deficiency—warfarin toxicity, sweet clover toxicityAdverse effects- anaphylactic reactions
  • VI. AnticoagulantsA. Heparinis a sulphtaed mucopolysaccharideMOA-enhances interaction between antithrombin and clotting factors; Inhibits fibrin induced platelet aggregationIndication- thrombosisADR-hemorrhage
  • B. Warfarin, coumarin derivativesMOA-prevent the resynthesis of vitamin KIndications - thrombosisADR-hemorrhageC. AspirinMOA-acetylates thromboxane synthase and reduce the synthesis of thromboxaneIndication-thrombosisADR-hemorrhage, peptic ulceration
  • VII. Fibrinolytics•Are drugs used to dissolve clots•Streptokinase, streptodornase, alteplase•MOA-activate plasminogen•Indication – thrombosis•ADR- bleedingVIII. Antifibrinolytics•Aminocaproic acid, tranexamic acid•MOA- competitive inhibition of the activation of plasminogen•Indication- post operative hemorrhage•ADR-diarrhea, hypotension
  • IX. HematinicsAre used to restore packed cell volume and HGBvaluesA. Iron salts-MOA- Hemoglobin formationIndications- commonly used in pigletsADR- necrosis of cells due to free radicals,hyperkalemia, overwhelming of macrophages,calcyphylaxis
  • B- Epoetin alphaIs a glycoproteinMOA-stimulation of bone marrow cellsIndication- chronic renal failureADR-hypersensitivity reaction
  • C- Anabolic steroidsStanzolol, oxymethonolMOA- stimulate the production oferythropoietinIndication-bone marrow depressionADR-sodium and water retentionD- Others—Vit. B12, pyridoxine, folic acid,copper, cobalt
  • X. Fluid and electrolyte therapyAre used to correct disorders of the intravascularvolume, interstitial fluid volume and electrolyteabnormalitiesA. Colloidesnatural- plasma, whole bloodsynthetic-hetastarch, dextran
  • HetastarchIs primarily amylopectin (98%)MOA-creates an osmotic pressureIndication-hypovolemiaAdverse effect-haemodilution; effect on bloodcoagulation
  • B. CrystalloidsLactated ringers, normosol, normal salineused to correct fluid deficits and electrolyte imbalances•Selection is based on the measured or estimatedsodium/potassium concentrations and by theosmolality of the serum and fluid.•Osmolality- defined as the number of solute particles perliter of solvent( Na, K, Glucose , Blood urea nitrogen• Normal serum – 290-310 mOSM/L•Indications- hyperosmolar serum, reduced tissue perfusion, dehydration•ADR-haemodilution
  • Rate and volume of administrationDepends on the degree of fluid loss(hemorrhage, vomiting, diarrhea)Rehydration- estimate the degree of interstitial fluid deficit Mucus membrane eye skin turgidity5% semi dry moist normal7% dry moist mild loss12% very dry dull/sunken considerable loss loss of consciousness, weak pulsemaintenance- ongoing and insensible losses ( 50ml/Kg per day Fever- 20 ml/Kg per day
  • XI. DiureticsAre drugs that increase water and sodium excretionA.Loop diureticsB.Furosemide, bumetanideMOA-inhibition of the sodium/potassium /chlorine co transport system at the loop of Henely;potassium excretion is a secondary effectIndications- heart failure, hypertension, oedemaADR-hyponatremia, hypokalemia, hypochloremia,dehydration
  • B. ThiazidesHydrochlorthiazide, bendroflumethiazideMOA-inhibition of sodium and chloride reabsorption at the distal convoluted tubule ; potassium excretion is asecondary effectIndications- heart failure, hypertension, oedemaADR-hyponatremia, hypochloremia, dehydration
  • C. Potassium sparingSpironolactoneMOA- Antagonises the action of aldosterone at thedistal convoluted tubuleIndications- hypertension, oedemaADR-hyponatremia, hyperkalemia, hypochloremia,dehydration
  • XII. AntidiureticsAre agents that cause retention of sodium and waterVasopressin, desmopressin, lypressinAre synthetic nanopeptidesMOA-smooth muscle contraction; reduce water extraction at the level of the collecting ductsIndication- diabetes insipidus (central)ADR-GIT smooth muscle contraction, water intoxication, hypertensionADH release stimulants chlorpropamide, clofibrate-cause an increase in ADHsecretion
  • XIII. Renal vasodilatorsRenal vasodilators Furosemide, Dopamine increase renal blood flow Indicated for Acute renal failure
  • XIV. Urine alkalinizers/acidifiersSodium bicarbonate, potassium citrateMOA-Alkalinze urineIndications-stones due to oxalates, uratesADR-alkalosisAmmonium chlorideMOA-acidify urineIndications-struvite stonesADR-acidosis
  • XV. Urethral sphincter muscle stimulantsIndications-incontinenceDiethylstilbesterol-femalesTestosterone -malesMOA- increase in sphincter muscle tone due to their anabolic effectsPhenylpropanolamineMOA-alpha agonistADR-CNS stimulation, restlessness, vasoconstriction
  • XVI. Urethral sphincter muscle relaxantsIndications- urine retentionPhenoxybenzamineMOA-alpha adrenergic antagonistADR-hypotensionBethenecol chlorideMOA-cholinergic agonistADR-increased secretions, prokinetic effects