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General Toxicology Toxic Responses of the Heart & Vascular System (II) Lec. 11 4 th Year 2018-2019 University of Mustansiriyah/College of Pharmacy Department of Pharmacology & Toxicology Lecturer: Rua Abbas Al-Hamdy. Objectives of lecture: Objectives of this lecture are to:
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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
Objectives of lecture: • Objectives of this lecture are to: • identify cardiotoxic chemicals. • determine cardiotoxic manifestations & the proposed mechanisms of cardiotoxicity for some selected chemicals.
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
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.
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.
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.
Inotropic drugs: • Cardiac glycosides • Catecholamines & sympathomimetics
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.
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.
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.
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.
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.
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.
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.
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.
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).
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).
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.
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.
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.
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
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.
Steroids & related hormones: Estrogens, progestins, androgens, & adrenocortical steroids are major steroid hormones produced by mammals including humans.
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.
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).
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.
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.
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.
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.
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.
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.
Patients with underlying cardiovascular disease may display arrhythmias under the treatment of thyroid hormones. • Thyroid hormones also alter Ca2+ homeostasis.
Cytokines: Cardiotoxicity of some selected cytokines are shown in Table 4. Table 4. Cardiotoxicity of selected cytokines
Industrial chemicals: • Solvents • Aldehydes & alcohols • Heavy metals
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.
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).
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.
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+.
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.