CARDIOVASCULAR DRUGSdr. Dian Nugrahenny, M.Biomed.

Department of PharmacologyFaculty of MedicineBrawijaya Universitydiannugr2407@gmail.com

BASIC ANATOMY AND PHYSIOLOGYFunctions 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 SYSTEMCardiacBlood vesselsBloodGuyton Textbook of Medical Physiology, 11th ed.

Guyton Textbook of Medical Physiology, 11th ed.

BASIC ANATOMY AND PHYSIOLOGYGuyton Textbook of Medical Physiology, 11th ed.

CARDIAC SYMPATHETIC AND PARASYMPATHETIC NERVESGuyton Textbook of Medical Physiology, 11th ed.

*ADRENERGIC SYSTEMReceptor SubtypeTissueEffectsAlpha 1Vascular smoothContractionmuscle

Beta 1HeartInc. Heart RateInc. Force of Contraction

Beta 2Bronchial smooth Relaxationmuscle

POSSIBLE MECHANISMS FOR INFLUENCING HEART FUNCTIONLllmann et al. 2000. Color Atlas of Pharmacology, 2nd ed. Thieme.

HYPERTENSIONPrimary (essential): 90%SecondaryVirtually no symptomsTreatment is usually life-longConsequences of hypertension: heart disease, kidney disease, blindness, stroke

INITIAL DRUG THERAPY CHOICESDiPiro et al. 2005. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. The McGraw-Hill Companies, Inc.

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

DIURETICSDrugs 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.

ACTION OF DIURETICSThiazides (e.g. HCT): act in the intermediate segment of distal tubules.Loop diuretics (e.g. furosemide): act in the thick portion of the ascending limb of Henles loop.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.

SIDE EFFECTS OF DIURETICS NURSING ALERTS

Side effectsNursing actionsRationaleIncrease urine outputGive in the early morning if ordered dailyPeak action will occur during waking hours & not interrupt with sleepKeep a bedpan within reach. Assist to the bathroom anyone who is elderly, weak, dizzy, or unsteady in walking.Mainly to avoid fallPostural hypotensionAssist the patient to get up slowlyAvoid fallingPossibility of dehydrationRecord fluid intake & output regularlyAvoid fluid volume depletion due to excessive diuresisHypo/Hyper-kalemiaMonitor serum potassium level (within 3.5-5 mEq)Avoid K depletion due to thiazide & loop diuretics or avoid K accumulation in patient taking K-sparing diuretics Electrolytes imbalanceMonitor K, Na, Cl, Mg & bicarbonate levelsAvoid electrolyte imbalance

CA2+-CHANNEL BLOCKER (CCB)Inhibit the influx of Ca2+ ions without affecting inward Na+ or outward K+ currents to a significant degree.

Hypotension, dizziness, weakness, peripheral edema, headache, heart failure, pulmonary edema, nausea, constipationBradycardia (Verapamil, Diltiazem)Tachycardia (Nifedipine & other dihydropyridines)SIDE EFFECTS OF CCB

*The older may have a greater hypotensive effect after taking CCBs than younger adults. The nurse must monitor them closely during dosage adjustments.Make position changes slowly to minimize hypotensive effects.Some patients may experience dizziness and light-headedness, especially during early therapy. The nurse should assist the patient with all ambulatory activities and instructs the patients to ask for help when getting out of bed or ambulating.CCB NURSING ALERTS

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS)

ACTION OF ANGIOTENSIN IIAngiotensin II receptor blocker (ARB)

Used to treat hypertension, heart failure, myocardial infarction, and nephropathyEnalapril 10-40 mg/day in 1 or 2 dosesLisinopril 10-40 mg once dailyPerindopril 2-8 mg dailyRamipril 1.25-10mg once dailyACE INHIBITORS

Used for hypertension, may be used as an alternative to ACE inhibitors in the management of heart failure and diabetic nephropathy.Irbesartan 150-300 mg once dailyLosartan 25-100 mg once dailyValsartan 80-160 mg once dailyAngiotensin II receptor blockers (ARBs)

ACE INHIBITOR ARB: NURSING ALERTSNote: The intestinal absorption of ACE inhibitors and ARBs may be reduced if taken with food.

Potential Adverse EffectsNursing ActionsACE inhibitors and ARBs may cause first dose hypotensionInstruct the patient to lie down if hypotension developsACE inhibitors may produce dry cough, due to accumulation of bradykininWarn patients about the possibility of cough. Consult the doctor if the cough is bothersome to the patient.ACE inhibitors may cause hyperkalemiaAvoid potassium supplements, potassium containing salt substitutes and potassium-sparing diureticsACE inhibitors and ARBs are contra-indicated in pregnancyAvoid these drugs in pregnancy

BETA-BLOCKERBy blocking cardiac -receptors, -Blockers serve to lower cardiac rate and lower the elevated blood pressure caused by high cardiac output.

The mechanism underlying their antihypertensive action via reduction of peripheral resistance is unclear.

*BETA BLOCKERS

DrugReceptors BlockedMaintenance Dosage in HypertensionAtenololBeta150mg daily poMetoprololBeta1100-200mg daily in one to two doses po200-400mg daily po (Slow release)CarvedilolBeta1 and 212.5-50mg bd poLabetololBeta1 and 2100-200mg bd po with foodPropranololBeta1 and 2160-320mg daily po

ADRENERGIC SYSTEMReceptor SubtypeTissueEffectsAlpha 1Vascular smoothContractionmuscle

Beta 1HeartInc. Heart RateInc. Force of Contraction

Beta 2Bronchial smooth Relaxationmuscle

Insulin secretionStimulation

BETA BLOCKERSSide Effects:BradycardiaHypotensionBronchospasmsGI disturbancesFatigue

Nursing Alerts:Caution patients not to stop taking them abruptly because that can precipitate angina and MIInstruct diabetics to monitor blood glucose levels more often at vulnerable times Screen for asthma patients on beta blockers

TREATMENT OF CHRONIC HYPERTENSION IN PREGNANCYDiPiro et al. 2005. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. The McGraw-Hill Companies, Inc.

ANTIANGINAL DRUGSNITRATESDrugs: nitroglycerin, ISDN, ISMN.As NO donors.The effect is more pronounced in venous than in arterial beds.

Nitrate Preparations and Dosage

Drug and dosage formRouteDosageGlyceryl TrinitrateSublingual tablet 500mcgSublingual1 tablet under the tongue immediately as requiredSpray 0.4mg/dose SublingualSpray 1-2 doses under tongueCapsule 2.5mg (Retard)Oral1-2 capsules 2-3 times a day

Nitrate Preparations and Dosage (Contd)

Drug and dosage formRouteDosageGlyceryl Trinitrate (Contd) Transdermal patches 5mg / 10mgTransdermal1 patch every 24 hoursIsosorbide MononitrateTablet 20mgOral20mg bd to tid / 40mg bdTablet 60mg (controlled release)Oral30-120mg in the morningCapsule 50mg (sustained release)Oral1-2 capsules in the morning

Nitrate Preparations and Dosage (Contd)

Drug and dosage formRouteDosageIsosorbide DinitrateTablet 10mgOral30-240mg in divided dosesTablet 40mg (sustained release)Oral20-40mg every 12 hoursCapsule 20mg (sustained release)Oral1 capsule bd or tid

Tolerance to nitrate can develop rapidlyThis may be due to depletion of sulfhydryl (S-H) groups in the vascular smooth muscle. These groups are needed to convert nitrate to NO.NITRATE-TOLERANCE

NITRATE: NURSING ALERTS

Potential Adverse EffectsNursing ActionsHeadacheInform patients that headache will diminish with continued drug use. Can be relieved by mild analgesics.Orthostatic hypotensionSlowly change from a sitting or lying position to an upright position. Advise the patient to lie or sit down if symptoms of hypotension (e.g. dizziness, lightheadedness) occur.ToleranceTo prevent tolerance, use the minimum effective dose. For long-acting preparations, they should be used on an intermittent schedule to allow at least 8 drug-free hours.

NITRATE: NURSING IMPLICATIONSTeach the patients:

NTG needs to absorb from mouth so dont swallow, may crush tab with teeth to speed absorption if pain is severe

If chest pain continues after taking 3 slow/sustained release (SL) tablets at 5-minute intervals then seek emergency care

Carry with you at all times

Keep in dark glass bottle and get new supply every 6 months

Take before any activity that usually precipitates chest pain

Side effects may include flushing, throbbing headache, hypotension, and tachycardia

May develop tolerance to NTG, so that many physicians suggest the patch removed at 10 pm for 6-8 hours without nitrates in system

Monitor BP and pain closely if IV route usedNITRATE: NURSING IMPLICATIONS (CONTD)

CONGESTIVE HEART FAILURERight Heart FailurePredominant: Sign: venous congestionSubcutaneous edemaAbdominal effusion (ascites)HepatomegalySplenomegalyLeft Heart FailurePredominant: SymptomDyspnea, orthopnea, cough (pulmonary edema)Inadequate tissue perfusion from a failing pump, volume overloadMajor causes: hypertension, myocardial infarction

DRUGS FOR HEART FAILURE3D:VasoDilators:VenodilatorsArteriolar dilatorsDiureticsDigitalis

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

Potensial side effect: hypotensionLllmann et al. 2000. Color Atlas of Pharmacology, 2nd ed. Thieme.

OTHER VASODILATORSHydralazine: Dilate arteriolesTreats hypertensionLess postural hypotensionMinoxidil: Dilate arteriolesFor severe hypertensionDiazoxide:Given i.v. causes prominent arteriolar dilationFor hypertensive crisesCan be used in the management of insulin-secreting pancreatic tumors.Nitroprusside sodium: Dilate venous and arteriolesGiven i.v. for hypertensive crises

DIGITALIS, CARDIAC GLYCOSIDESIn severe cases of myocardial insufficiency, digitalis may be added to augment cardiac force (positive inotrope) and to relieve the symptoms of insufficiency.Very narrow therapeutic index.Very long half-life.Digoxin has many drug interactions: diuretics,verapamil, amiodarone, etc.

PROCESSES IN MYOCARDIAL CONTRACTION AND RELAXATIONLllmann et al. 2000. Color Atlas of Pharmacology, 2nd ed. Thieme.

SIDE EFFECTS OF DIGITALISDysrhythmiasBradycardiaToxicity very narrow therapeutic index hypokalemia makes it easier for toxicity to occurAnorexia, nausea, vomitingDisturbances of color visionFatigue

Withhold the drug & contact the physician if there are any signs of digoxin toxicity or marked changes in the pulse rate/rhythm (bradycardia)

Monitor digoxin levels closely: should be smaller than 2 ng/mL

Older adults are particularly prone to digoxin toxicity

Screen for factors that potentiate digitalis toxicity: hypokalemia, impaired renal function, oral antibiotics, quinidine, amiodarone, Ca++ channel blockersDIGITALIS: NURSING ALERTS

CARDIAC ARRHYTHMIASAutonomic nervous system disordersAltered ionic permeability of cardiac membranesFactors: trauma; hypoxia; infection; metabolic disease; drugs and toxinsIntrinsic cardiovascular disease

CARDIAC IMPULSE GENERATION AND CONDUCTION

ANTI-ARRHYTHMIA DRUGS (AARD): GENERAL MECHANISMS OF ACTIONChange gating properties of cardiac ion channels (Na+, Ca2+, K+) directlyChange neuromodulatory control of cardiac ion channel opening/closing

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

Antiarrhythmic drugs are capable of causing new arrhythmias, as well as an exacerbation of existing arrhythmias.

Older adults taking antiarrhythmic drugs are at greater risk for adverse reactions such as development of additional arrhythmias or aggravating of existing arrhythmias, hypotension, and congestive heart failure.

Careful monitoring (HR, BP, ECG) is necessary for early identification and management of adverse effects.AARDS: NURSING ALERTS

HEMOSTASIS AND THROMBOSISC. SECONDARY HEMOSTASISlateletsadhesionADP, adenosine diphosphate; t-PA, tissue type plasminogen activator

PARENTERAL ANTICOAGULANTSHeparin Administered by injectionHelps inactivate thrombin, factor Xa and othersHalf-life is short

Therapeutic Uses:Open heart surgeryDeep Vein ThrombosisAcute MI

PARENTERAL ANTICOAGULANTSSide EffectsBleedingThrombocytopenia heparin inducedHypersensitivityTherapeutic effect is monitored by PTT (partial thromboplastin time) every 6 hours and dose adjusted to achieve PTT 1.5-2.0 times normal levelNursing Alerts:Monitor for signs and symptoms of bleeding: low HR, hypotension, tachycardia, epistaxisAvoid injuriesHold injection sites longer than usual

ORAL ANTICOAGULANTSWarfarin

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 Uses: Long-term prophylaxis of thrombosis, e.g. in patients with prosthetic heart valves/atrial fibrillation.

ORAL ANTICOAGULANTSWarfarin has MANY drug and herb interactionsHemorrhageWarfarin is contraindicated in pregnancyMust monitor PT (prothrombin time)/INR (international normalized ratio, contains a correction factor for PT)Vitamin K can be given in case of overdose

DRUGS INTERACT WITH WARFARINAbciximabAcetaminophenAlcohol (acute and chronic)AllopurinolAminodaroneAminoglutethimideAmobarbitalAnabolic steroidsAspirinAzathioprineButabarbitalButalbitalCarbamazepineCefoperazoneCefotetanCefoxitinCeftriaxoneChenodiolChloral hydrateChloramphenicolChlorpropamideChlorthalidoneCholestyramineCimetidineCiprofloxacinClarithromycinClofibrate

CorticotropinCortisoneCoumadinCyclophosphamideDanazolDextranDextrothyroxineDiazoxideDiclofenacDicloxaxillinDiflunsialDisulframDoxycyclineErythromycinEthacrynic acidEthchlorvynolFenoprofenFluconazoleFluorouracilGemfibrozilGlucagonGlutethimideGriseofulvinHaloperidolHalothaneHeparin

OfloxacinOlsalazineOmeprazoleOxaprozinOxymetholoneParaldehydeParoxetinePenicillin GPentobarbitalPentoxifyllinePhenobarbitalPhenylbutazonePhenytoinPiperacillinPiroxicamPrednisonePrimidonePropafenonePropoxyphenePropranololPropylthiouracilPhytonadioneQuinidineQuinineRanitidineRifampinIbuprofenIfosamideIndomethacinInfluenza virus vaccineItraconazoleKetoprofenKetorolacLevamisolLevothyroxineLiothyronineLovastatinMefenamicMeprobamateMethimazoleMethyldopaMethylphenidateMethylsalicylateMiconzaleMetronidazoleMiconazoleMoricizine HClNafcillinNalidixic acidNaproxenNeomycinNorfloxacinSecobarbitalSertalineSimvastatinSpironolactoneStanozololStreptokinaseSucralfateSulfamethizoleSulfamethoxazoleSulfinpyrazoneSulfinpyrazoneSulfisoxazoleSulindacTamoxifenTetracyclineThyroid hormoneTicacillinTiclopidinet-PATolbutamideTrazodoneTrimethoprim-sulfamethoxazoleUrokinaseValproateVitamin CVitamin E

WARFARIN AND G HERBSGarlic (Allium sativum) 2 case reports. Continuing ingestion of high levels of garlic or garlic oil can decrease platelet aggregation.

Ginger (Zingiber officinalis) Inconclusive results in studies in healthy volunteers but case reports exist.

Ginkgo (Ginkgo biloba) The extract inhibits thromboxane and prostacyclin in diabetics. A case report suggests interaction.

Green tea (Camellia sinensis) Inhibits platelet synthesis of thromboxane.Chavez, Life Sci 2006; 78:2146-57

ORAL ANTICOAGULANTSNursing Implications:Teach the patients: Observe for signs of bleeding and report bleeding from gums/nose or in stool/urineUse soft toothbrushAvoid using aspirin or NSAIDS or any meds that may potentiate bleedingFrequent lab tests are necessary to monitor

ANTIPLATELET DRUGSAspirinPrevention of thrombosis in arteriesSuppresses platelet aggregation due to inhibition of thromboxan (TXA2) synthesisTherapeutic Uses: prophylaxis of MI, prevent reinfarction in patients with acute MI, prevent strokeLow dose - not greater than 325 mg/daySide Effects: GI bleeding, bronchospasm

Clopidogrel (Plavix)Adenosine diphosphate receptor (ADP) antagonistIrreversible blocking of ADP receptors on the platelet surface Prevent ADP-stimulated aggregationTherapeutic Uses: prevention of stroke, vascular death & MISide Effects:Hemorrhage (GI & Intracranial)GI side effectsANTIPLATELET DRUGS

ANTIPLATELET DRUGSNursing Implications:Screen for asthma patients on aspirinTeach the patients: Drugs should be taken after meal due to GI irritationObserve for signs of bleeding and report bleeding from gums/nose or in stool/urineUse soft toothbrush

SEMANGAT BELAJAR!!!

Cardiac sympathetic and parasympathetic nerves. (The vagus nerves to the heart are parasympathetic nerves.)

For given levels of input atrial pressure, the amount of blood pumped each minute (cardiac output) often can be increased more than 100 per cent by sympathetic stimulation. By contrast, the output can be decreased to as low as zero or almost zero by vagal (parasympathetic) stimulation.

Strong sympathetic stimulation can increase the heart rate in young adult humans from the normal rate of 70 beats per minute up to 180 to 200 and, rarely, even 250 beats per minute. Also, sympathetic stimulation increases the force of heart contraction to as much as double normal, thereby increasing the volume of blood pumped and increasing the ejection pressure.

The vagal fibers are distributed mainly to the atria and not much to the ventricles, where the power contraction of the heart occurs. This explains the effect of vagal stimulation mainly to decrease heart rate rather than to decrease greatly the strength of heart contraction. *The pumping capacity of the heart is regulated by sympathetic and parasympathetic nerves. Drugs capable of interfering with autonomic nervous function therefore provide a means of influencing cardiac performance. Thus, anxiolytics of the benzodiazepine type, such as diazepam, can be employed in myocardial infarction to suppress sympathoactivation due to life-threatening distress. Under the influence of antiadrenergic agents, used to lower an elevated blood pressure, cardiac work is decreased. Ganglionic blockers are used in managing hypertensive emergencies. Parasympatholytics and -blockers prevent the transmission of autonomic nerve impulses to heart muscle cells by blocking the respective receptors.

An isolated mammalian heart whose extrinsic nervous connections have been severed will beat spontaneously for hours if it is supplied with anutrient medium via the aortic trunk and coronary arteries (Langendorff preparation). In such a preparation, only those drugs that act directly on cardiomyocytes will alter contractile force and beating rate.

Parasympathomimetics and sympathomimetics act at membrane receptors for visceromotor neurotransmitters. The plasmalemma also harbors the sites of action of cardiac glycosides (the Na/K-ATPases), of Ca2+ antagonists (Ca2+ channels), and of agents that block Na+ channels (local anesthetics). An intracellular site is the target for phosphodiesterase inhibitors (e.g., amrinone).

Mention should also be made of the possibility of affecting cardiac function in angina pectoris or congestive heart failure by reducing venous return, peripheral resistance, or both, with the aid of vasodilators; and by reducing sympathetic drive applying -blockers.*BP = CO x total peripheral resistanceCO = HR x SV

BP: blood pressureCO: cardiac output, is commonly used to measure the performance of the heart.HR: heart rateSV: stroke volume, is the volume of blood ejected from the heart with each contraction.*Mobilization of edemasIn edema there is swelling of tissues due to accumulation of fluid, chiefly in the extracellular (interstitial) space. When a diuretic is given, increased renal excretion of Na+ and H2O causes a reduction in plasma volume with hemoconcentration. As a result, plasma protein concentrationrises along with oncotic pressure. As the latter operates to attract water, fluid will shift from interstitium into the capillary bed. The fluid content of tissues thus falls and the edemas recede. The decrease in plasma volume and interstitial volume means a diminution of the extracellular fluid volume (EFV). Depending on the condition, drugs of choice: thiazides, loop diuretics, aldosterone antagonists, and osmotic diuretics.

Antihypertensive therapy. Diuretics have long been used as drugs of first choice for lowering elevated blood pressure. Even at low dosage, they decrease peripheral resistance (without significantly reducing EFV) and thereby normalize blood pressure.

Therapy of congestive heart failure.By lowering peripheral resistance, diuretics aid the heart in ejecting blood (reduction in afterload; cardiac output and exercise tolerance are increased. Due to the increased excretion of fluid, EFV and venous return decrease (reduction in preload). Symptoms of venous congestion, such as ankle edema and hepatic enlargement, subside. The drugs principally used are thiazides (possibly combined with K+-sparing diuretics) and loop diuretics.*Ca-channel blockerDuring electrical excitation of the cell membrane of heart or smooth muscle, different ionic currents are activated, including an inward Ca2+ current. The term Ca2+ antagonist is applied to drugs that inhibit the influx of Ca2+ ions without affecting inward Na+ or outward K+ currents to a significant degree. Therapeutically used Ca2+ antagonists can be divided into two groups according to their effects on heart and vasculature.

1. Dihydropyridine derivatives.The dihydropyridines, e.g., nifedipine, are uncharged hydrophobic substances. They induce a relaxation of vascular smooth muscle in arterial beds. An effect on cardiac function is practically absent at therapeutic dosage. They are thus regarded as vasoselective Ca2+ antagonists. Because of the dilatation of resistance vessels, blood pressure falls. Cardiac afterload is diminished and, therefore, also oxygen demand. Spasms of coronary arteries are prevented.Indications for nifedipine include angina pectoris and hypertension (when applied as a sustained release preparation). In angina pectoris,it is effective when given either prophylactically or during acute attacks. Adverse effects are palpitation (reflex tachycardia due to hypotension), headache, and pretibial edema.

2. Verapamil and other cationic amphiphilic Ca2+ antagonists. It exerts inhibitory effects not only on arterial smooth muscle, but also on heart muscle. In the heart, Ca2+ inward currents are important in generating depolarization of sinoatrial node cells (impulse generation), in impulse propagation through the AV- junction (atrioventricular conduction), and in electromechanical coupling in the ventricular cardiomyocytes. Verapamil thus produces negative chrono-, dromo-, and inotropic effects.Indications. Verapamil is used as an antiarrhythmic drug in supraventricular tachyarrhythmias. In atrial flutter or fibrillation, it is effective in reducing ventricular rate by virtue of inhibiting AV-conduction. Verapamil is also employed in the prophylaxis of angina pectoris attacks and the treatment of hypertension. Adverse effects: Because of verapamils effects on the sinus node, a drop in blood pressure fails to evoke a reflex tachycardia. Heart rate hardly changes; bradycardia may even develop. AV-block and myocardial insufficiency can occur. Patients frequently complain of constipation.

Diltiazem is a cationic amphiphilic benzothiazepine derivative with an activity profile resembling that of verapamil.*Angiotensin-converting enzyme (ACE) is a component of the antihypotensive renin-angiotensin-aldosterone (RAA) system. Renin is produced by specialized cells in the wall of the afferent arteriole of the renal glomerulus. These cells belong to the juxtaglomerular apparatus of the nephron, the site of contact between afferent arteriole and distal tubule, and play an important part in controlling nephron function.

Stimuli eliciting release of renin are: a drop in renal perfusion pressure, decreased rate of delivery of Na+ or Cl to the distal tubules, as well as -adrenoceptor-mediated sympathoactivation. The glycoprotein renin enzymatically cleaves the decapeptide angiotensin I from its circulating precursor substrate angiotensinogen. ACE, in turn, produces biologically active angiotensin II (ANG II) from angiotensin I (ANG I).

ACE is a rather nonspecific peptidase that can cleave C-terminal dipeptides from various peptides (dipeptidyl carboxypeptidase). As kininase II, itcontributes to the inactivation of kinins, such as bradykinin that has vasodilation effects. ACE is also present in blood plasma; however, enzyme localized in the luminal side of vascular endothelium is primarily responsible for the formation of angiotensin II. The lung is rich in ACE, but kidneys, heart, and other organs also contain the enzyme.

ACE inhibitors, such as captopril and enalaprilat, the active metabolite of enalapril, occupy the enzyme as false substrates. Affinity significantly influences efficacy and rate of elimination. Enalaprilat has a stronger and longer-lasting effect than does captopril. Indications are hypertension and cardiac failure. Lowering of an elevated blood pressure is predominantly brought about by diminished production of angiotensin II. Impaired degradation of kinins that exert vasodilating actions may contribute to the effect. In heart failure, cardiac output rises again because ventricular afterload diminishes due to a fall in peripheral resistance. Venous congestion abates as a result of (1) increased cardiac output and (2) reduction in venous return (decreased aldosterone secretion, decreased tonus of venous capacitance vessels).Undesired effects. Drugs can induce arterial hypotension. Dry cough is a fairly frequent side effect, possibly caused by reduced inactivation of kinins in the bronchial mucosa. Cough is rare in domestic animals.Of the ACE inhibitors, enalapril, benazapril, and imidapril have been approved to treat dogs with heart failure in Canada. Only enalapril is approved in US.*Angiotensin II can raise blood pressure in different ways, including (1) vasoconstriction in both the arterial and venous limbs of the circulation; (2) stimulation of aldosterone secretion, leading to increased renal reabsorption of NaCl and water, hence an increased blood volume; (3) a central increase in sympathotonus and, peripherally, enhancement of the release and effects of norepinephrine.

Antagonists at angiotensin II receptors.Angiotensin II receptor blockers (ARBs) directly block the angiotensin II type 1 (AT1) receptor that mediates the known effects of angiotensin II in humans: vasoconstriction, aldosterone release, sympathetic activation, antidiuretic hormone release, and constriction of the efferent arterioles of the glomerulus. They do not block the angiotensin II type 2 (AT2) receptor. Therefore, beneficial effects of AT2 receptor stimulation (i.e., vasodilation, tissue repair, and inhibition of cell growth) remain intact when ARBs are used.They do not inhibit degradation of kinins and cough is not a frequent side-effect.*-Sympatholytics (-Blockers)-Sympatholytics are antagonists of norepiphephrine and epinephrine at -adrenoceptors; they lack affinity for -receptors.Therapeutic effects. -Blockers protect the heart from the oxygen-wasting effect of sympathetic inotropism by blocking cardiac -receptors;thus, cardiac work can no longer be augmented above basal levels (the heart is coasting). This effect is utilized prophylactically in angina pectoris to prevent myocardial stress that could trigger an ischemic attack. -Blockers also serve to lower cardiac rate (sinus tachycardia) and elevated blood pressure due to high cardiac output. The mechanism underlying their antihypertensive action via reduction of peripheral resistance is unclear. Applied topically to the eye, -blockers are used in the management of glaucoma; they lower production of aqueous humor without affecting itsdrainage.

Undesired effects. The hazards of treatment with -blockers become apparent particularly when continuous activation of -receptors is needed in order to maintain the function of an organ.

Congestive heart failure: In myocardial insufficiency, the heart depends on a tonic sympathetic drive to maintain adequate cardiac output. Sympathetic activation gives rise to an increase in heart rate and systolic muscle tension, enabling cardiac output to be restored to a level comparable to that in a healthy subject. When sympathetic drive is eliminated during -receptor blockade, stroke volume and cardiac rate decline, a latent myocardial insufficiency is unmasked, and overt insufficiency is exacerbated.On the other hand, clinical evidence suggests that -blockers produce favorable effects in certain forms of congestive heart failure (idiopathic dilated cardiomyopathy).*Methyldopa is an alpha-2-adrenoceptor agonist (centrally-acting sympatholytic vasodilator, inhibits sympathetic outflow from CNS). It is used very occassionally for the treatment of hypertension.*Organic NitratesDue to a decrease in both venous return (preload) and arterial afterload, cardiac work is decreased. As a result, the cardiac oxygen balance improves. Spasmodic constriction of larger coronary vessels (coronary spasm) is prevented.

Organic nitrates are used chiefly in angina pectoris, less frequently in severe forms of chronic and acute congestive heart failure. Continuous intake of higher doses with maintenance of steady plasma levels leads to loss of efficacy, in as much as the organism becomes refractory (tachyphylactic). This nitrate tolerance can be avoided if a daily nitrate-free interval is maintained, e.g., overnight.

Mechanism of action. The reduction in vascular smooth muscle tone is presumably due to activation of guanylate cyclase and elevation of cyclic GMP levels. The causative agent is most likely nitric oxide (NO) generated from the organic nitrate. NO is a physiological messenger molecule that endothelial cells release onto subjacent smooth muscle cells (endothelium-derived relaxing factor, EDRF).*Arteriolar vasodilators are given to lower blood pressure in hypertension, to reduce cardiac work in angina pectoris, and to reduce ventricular afterload (pressure load) in cardiac failure.Venous vasodilators are used to reduce venous filling pressure (preload) in angina pectoris or cardiac failure. *The signal triggering contraction is a propagated action potential (AP) generated in the sinoatrial node. Depolarization of the plasmalemma leads to a rapid rise in cytosolic Ca2+ levels, which causes the contractile filaments to shorten (electromechanical coupling). The level of Ca2+ concentration attained determines the degree of shortening, i.e., the force of contraction. Sources of Ca2+ are: a) extracellular Ca2+ entering the cell through voltage-gated Ca2+ channels; b) Ca2+ stored in membranous sacs of the sarcoplasmic reticulum (SR); c) Ca2+ bound to the inside of the plasmalemma. The plasmalemma of cardiomyocytes extends into the cell interior in the form of tubular invaginations (transverse tubuli).

The trigger signal for relaxation is the return of the membrane potential to its resting level. During repolarization, Ca2+ levels fall below the threshold for activation of the myofilaments (3.107 M), as the plasmalemmal binding sites regain their binding capacity; the SR pumps Ca2+ into its interior; and Ca2+ that entered the cytosol during systole is again extruded by plasmalemmal Ca2+-ATPases with expenditure of energy. In addition, a carrier (antiporter), utilizing the transmembrane Na+ gradient as energy source, transports Ca2+ out of the cell in exchange for Na+ moving down its transmembrane gradient (Na+/Ca2+ exchange). *If the inotropic, therapeutic dose is exceeded by a small increment, signs of poisoning appear: arrhythmia and contracture. The narrow therapeutic margin can be explained by the mechanism of action.

Cardiac glycosides (CG) bind to the extracellular side of Na+/K+-ATPases of cardiomyocytes and inhibit enzyme activity. This inhibits Na+ from leaving the cell via pump. Na+ utilizes the Na+/Ca2+ exchange mechanism to enable Na+ to exit the cell however in return Ca2+ enters the cells. The increase of cytosolic Ca2+ promotes a positive inotropic response.

When too many ATPases are blocked, K+ and Na+ homeostasis is deranged; the membrane potential falls, arrhythmias occur. Flooding with Ca2+ prevents relaxation during diastole, resulting in contracture.*The CNS effects of CG are also due to binding to Na+/K+-ATPases. Enhanced vagal nerve activity causes a decrease in sinoatrial beating rate and velocity of atrioventricular conduction. In patients with heart failure, improved circulation also contributes to the reduction in heart rate. Stimulation of the area postrema leads to nausea and vomiting. Disturbances in color vision are evident. *Antiarrhythmic DrugsThe electrical impulse for contraction (propagated action potential) originates in pacemaker cells of the sinoatrial node and spreads through theatria, atrioventricular (AV) node, and adjoining parts of the His-Purkinje fiber system to the ventricles. Irregularities of heart rhythm can interfere dangerously with cardiac pumping function.

I. Drugs for selective control of sinoatrial and AV nodes. In some forms of arrhythmia, certain drugs can be used that are capable of selectively facilitating and inhibiting (green and red arrows, respectively) the pacemaker function of sinoatrial or atrioventricular cells.

Sinus bradycardia. An abnormally low sinoatrial impulse rate (100 beats/min). -Blockers eliminate sympathoexcitation and decrease cardiac rate.

Atrial flutter or fibrillation. An excessive ventricular rate can be decreased by verapamil or cardiac glycosides. These drugs inhibit impulse propagation through the AV node, so that fewer impulses reach the ventricles.

II. Nonspecific drug actions on impulse generation and propagation.Impulses originating at loci outside the sinus node are seen in supraventricular or ventricular extrasystoles, tachycardia, atrial or ventricular flutter, and fibrillation. In these forms of rhythm disorders, antiarrhythmics of the local anesthetic, Na+-channel blocking type are used for both prophylaxis and therapy. Local anesthetics inhibit electrical excitation of nociceptive nerve fibers; concomitant cardiac inhibition (cardiodepression) is an unwanted effect.However, in certain types of arrhythmias, this effect is useful.Local anesthetics are readily cleaved and unsuitable for oral administration (procaine, lidocaine). Given judiciously, intravenous lidocaine is an effective antiarrhythmic. Procainamide and mexiletine, congeners endowed with greater metabolic stability, are examples of orally effective antiarrhythmics.The desired and undesired effects are inseparable. Thus, these antiarrhythmics not only depress electrical excitability of cardiomyocytes (negativebathmotropism, membrane stabilization), but also lower sinoatrial rate (neg. chronotropism), AV conduction (neg. dromotropism), and force of contraction (neg. inotropism). Interference with normal electrical activity can, not too paradoxically, also induce cardiac arrhythmias arrhythmogenic action.

Inhibition of CNS neurons is the underlying cause of neurological effects such as vertigo, confusion, sensory disturbances, and motor disturbances (tremor, giddiness, ataxia, convulsions).*Diagrammatic representation of the normal hemostatic process. A, After vascular injury, local neurohumoral factors induce a transient vasoconstriction. B, Platelets adhere to exposed extracellular matrix (ECM) via von Willebrand factor (vWF) and are activated, undergoing a shape change and granule release; released adenosine diphosphate (ADP) and thromboxane A2 (TxA2 ) lead to further platelet aggregation to form the primary hemostatic plug.C, Local activation of the coagulation cascade (involving tissue factor and platelet phospholipids) results in fibrin polymerization, "cementing" the platelets into a definitive secondary hemostatic plug. D, Counter-regulatory mechanisms, such as release of tissue type plasminogen activator (t-PA) (fibrinolytic) and thrombomodulin (interfering with the coagulation cascade), limit the hemostatic process to the site of injury.**