Objectives of lecture: Objectives of this lecture are to: identify cardiotoxic chemicals.

1. General ToxicologyToxic Responses of the Heart & Vascular System (II)Lec. 114th Year2018-2019University of Mustansiriyah/College of PharmacyDepartment of Pharmacology & ToxicologyLecturer: Rua Abbas Al-Hamdy

2. Objectives of lecture: • Objectives of this lecture are to: • identify cardiotoxic chemicals. • determine cardiotoxic manifestations & the proposed mechanisms of cardiotoxicity for some selected chemicals.

3. Cardiotoxic chemicals: • Alcohol • Pharmaceutical chemical: • Antiarrythmic agents • Inotropic drugs • Central nervous system acting drugs • Local anesthetics • Antineoplastic drugs • Antibacterial drugs • Antifungal drugs • Antiviral drugs • Naturally occurring substances • Industrial chemicals

4. Alcohol & alcoholic cardiomyopathy: • Clinically, the most recognized toxicologic cardiomyopathy is often referred to as alcoholic cardiomyopathy (ACM), which is characterized by an increase in myocardial mass, dilation of the ventricles, ventricular dysfunction, & heart failure. • Clinical data have shown that ACM typically is seen after a long term of consistent consumption of at least 80 g of alcohol per day.

5. The generation of reactive oxidative metabolites from the biotransformation of ethanol has been suggested to be a major contributing factor for ACM, because these metabolites lead to lipid peroxidation of cardiac myocytes or oxidation of cytosolic & membraneous protein thiols.

6. Antiarrhythmic agents: • Antiarrhythmic drugs have historically been classified based upon a primary mechanism of action: • Na+channel blockers (class I), • β-adrenergic blockers (class II), • drugs that prolong action potential duration, especially K+channel blockers (class III), & • Ca2+channel blockers (class IV). • Cardiotoxicity of antiarrhythmic drugs is summarized in Table 1.

7. Table 1. Cardiotoxicity of antiarrhythmic agents

8. Inotropic drugs: • Cardiac glycosides • Catecholamines & sympathomimetics

9. Cardiac glycosides: • These (digoxin & digitoxin) are inotropic drugs used for the treatment of congestive heart failure. • The mechanism of inotropic action of cardiac glycosides is shown in Figure 1. • Cardiotoxicity may result from Ca2+overload. The principal adverse cardiac effects of cardiac glycosides include slowed AV conduction with potential block, ectopic beats, & bradycardia.

10. Cardiac glycosides also exhibit parasympathomimetic activity through vagal stimulation & facilitation of muscarinic transmission; however, at higher doses, sympathomimetic effects may occur as sympathetic outflow is enhanced.

11. Figure 1. Mechanism of action of digoxin)

12. Catecholamines & sympathomimetics: • High circulating concentrations of epinephrine (adrenaline) & norepinephrine (noradrenaline) & high doses of synthetic catecholamines, such as isoproterenol, may cause cardiac myocyte death. • Catecholamine-induced cardiotoxicity involves pronounced pharmacological effects, including increased heart rate, enhanced myocardial oxygen demand, & an overall increase in systolic arterial blood pressure.

13. More selective β2-adrenergic receptor agonists are used for bronchodilatory effects in asthma eg, albuterol, fenoterol, metaproterenol, salmeterol, & terbutaline. • High oral doses of albuterol or terbutaline or inhalation doses of these drugs may lead to nonselective activation of β1-adrenergic receptors in the heart with subsequent tachycardia.

14. Sympathomimetic drugs that are more selective for α-adrenergic receptors include the nasal decongestants eg, ephedrine, phenylephrine, & pseudoephedrine. As with the asthma drugs, at high doses these nasal decongestants can produce tachycardia.

15. Central nervous system acting drugs: • Some of central nervous system (CNS)-acting drugs have considerable effects on the cardiovascular system, including: • tricyclic antidepressants (TCAs), • general anesthetics, & • antipsychotic drugs.

16. Tricyclic antidepressants (TCAs): • TCAs ,eg, amitriptyline, desipramine, imipramine, & protriptyline have significant cardiotoxic effects, particularly in cases of overdose. • The effects of TCAs on the heart include ST segment elevation, QT prolongation, supraventricular & ventricular arrhythmias (including torsades de pointes, & sudden cardiac death. • TCAs cause postural hypotension—the most prevalent cardiovascular effect.

17. Although many of these adverse effects are related to the quinidine-like actions, anticholinergic effects, & adrenergic actions of these drugs, the tricyclics also have direct actions on cardiac myocytes & Purkinje fibers, including depression of inward Na+& Ca2+& outward K+currents.

18. Antipsychotic drugs: • Phenothiazines (eg, chlorpromazine & thioridazine) may exert direct effects on the myocardium, including negative inotropic actions & quinidine-like effects. • Some ECG changes induced by these drugs include prolongation of the QT & PR intervals, blunting of T waves, & depression of the ST segment. • Through anticholinergic actions, clozapine can produce substantial elevations in heart rate (tachycardia).

19. General anesthetics: • General anesthetics (eg, enflurane, desflurane, halothane, & methoxyflurane) have adverse cardiac effects, including reduced cardiac output by 20%–50%, depression of contractility, & production of arrhythmias. • These anesthetics may sensitize the heart to the arrhythmogenic effects of endogenous epinephrine or to β-receptor agonists. • Halothane has been found to block the L-type Ca2+channel, & to disrupt Ca2+homeostasis associated with the sarcoplasmic reticulum (SR).

20. Propofol is an intravenously administered general anesthetic that also decreases cardiac output & blood pressure. • In addition, propofol causes a negative inotropic effect by its direct action on cardiac myocytes. Propofol has been shown to antagonize β-adrenergic receptors, & inhibit L-type Ca2+ current.

21. Local anesthetics: In general, local anesthetics have few undesirable cardiac effects. However, when high systemic concentrations of cocaine & procainamide are attained, these chemicals may have prominent adverse effects on the heart.

22. Cocaine: Cocaine has sympathomimetic, & proarrhythmogenic effects on the heart. In addition, cocaine causes cardiac myocyte death & myocardial infarction. Other local anesthetic drugs: Other local anesthetic drugs (eg, etidocaine, lidocaine, & procainamide) cause decreases in electrical excitability, conduction rate, & have proarrhythmogenic effects, likely through Na+ channel blockade.

23. Cardiotoxicity of other key pharmaceutical agents: Cardiotoxicity of other key pharmaceutical agents is shown in Table 2. Table 2. Cardiotoxicity of some key pharmaceutical agents

27. Natural products: Natural products include naturally occurring catecholamines, hormones, & cytokines, as well as animal & plant toxins. Many of these products have been shown to cause cardiac toxic responses.

28. Steroids & related hormones: Estrogens, progestins, androgens, & adrenocortical steroids are major steroid hormones produced by mammals including humans.

29. Estrogens: • Endogenous estrogens include 17β-estradiol, estrone, & estriol. • Synthetic estrogens: eg, diethylstilbestrol, ethinyl, & estradiol. • Estrogens (frequently in combination with progestins) have been used for many years as oral contraceptive drugs. • The older versions of estrogenic oral contraceptives that contained high amounts of estrogens were associated with increased risk of coronary thrombosis & myocardial infarction.

30. However, lower doses of estrogens have been found by numerous investigators to impart protective effects on the cardiovascular system, including antiapoptotic effects, & beneficial effects on lipid metabolism such as decreased low density lipoproteins (LDL cholesterol) & increased high-density lipoproteins (HDL cholesterol).

31. Progestins: • Examples of progestins are desogestrel, hydroxyprogesterone, medroxyprogesterone,, norgestimate, norgestrel, & progesterone. • Very little is known about the direct effects of progestins on the heart. Although progestins could exert deleterious effects on the heart, more studies are required to investigate mechanisms.

32. Androgens: • Natural androgens (eg, dihydrotestosterone, & testosterone). • Synthetic androgens (eg, danazol, methenolone, methyltestosterone, & nandrolone). • Anabolic-androgenic steroids have been associated with alterations in lipid metabolism, including increased LDL cholesterol & decreased HDL cholesterol; therefore, these chemicals may predispose individuals to atherosclerosis.

33. In humans, high-dose anabolic-androgenic steroid use has been associated with cardiac hypertrophy & myocardial infarction. • However, the mechanisms responsible for the cardiotoxic effects of anabolic-androgenic steroids remain poorly understood.

34. Glucocorticoids & mineralocorticoids: • Glucocorticoids & mineralocorticoids are primarily synthesized in the adrenal glands. • Naturally occurring glucocorticoids include corticosterone, cortisone, & hydrocortisone (cortisol), & the mineralocorticoid is aldosterone. • The primary glucocorticoids used systemically include cortisone, hydrocortisone, dexamethasone, methylprednisolone, prednisolone, & prednisone.

35. Both aldosterone & glucocorticoids appear to stimulate cardiac fibrosis by regulating cardiac collagen expression independently of hemodynamic alterations. • Furthermore, aldosterone & glucocorticoids induce hypertrophic growth of cardiac myocytes.

36. Thyroid hormones: • These include thyroxine (T4) & triiodothyronine (T3). These hormones exert profound effects on the cardiovascular system. • Hypothyroid states are associated with decreased heart rate, contractility, & cardiac output; whereas hyperthyroid states are associated with increased heart rate, contractility, cardiac output, ejection fraction, & heart mass.

37. Patients with underlying cardiovascular disease may display arrhythmias under the treatment of thyroid hormones. • Thyroid hormones also alter Ca2+ homeostasis.

38. Cytokines: Cardiotoxicity of some selected cytokines are shown in Table 4. Table 4. Cardiotoxicity of selected cytokines

39. Industrial chemicals: • Solvents • Aldehydes & alcohols • Heavy metals

40. Solvents: • Industrial solvents can exert adverse effects on the heart directly or indirectly; both are related to their inherent lipophilicity. • Solvents may affect cardiac physiological functions by directly dispersing into plasma membranes. • However, solvents may disrupt sympathetic & parasympathetic control of the heart as well as cause release of circulating hormones such as catecholamines.

41. Alcohols & aldehydes: • Unlike alcohols, the sympathomimetic activity of aldehydes decreases with increased chain length. • The acute cardiodepressant effects of alcohols & aldehydes may be related to inhibition of intracellular Ca2+ transport &/or generation of oxidative stress. • The common industrial alcohols include methanol (methyl alcohol or wood alcohol) & isopropyl alcohol (isopropanol).

42. Methanol is metabolized by alcohol dehydrogenase & aldehyde dehydrogenase to formaldehyde & formic acid, & often causes reduction in heart rate. • Isopropanol is metabolized to acetone which is metabolized to formic acid & acetic acid, which have the potential to induce mild acidosis. Tachycardia is the most prominent clinical finding of isopropanol exposure.

43. Heavy metals: • The most common heavy metals that have been associated with cardiotoxicity are cadmium, lead, & cobalt. • These metals exhibit negative inotropic & dromotropic effects & can also produce structural changes in the heart. • The cardiotoxic effects of heavy metals are attributed to their ability to form complexes with intracellular macromolecules & their ability to antagonize intracellular Ca2+.

44. Chronic exposure to cadmium has been reported to cause cardiac hypertrophy. • Lead has an arrhythmogenic sensitizing effect on the myocardium. In addition, lead has been reported to cause degenerative changes in the heart.