Xenobiotics may produce adverse effects on the cardiovascular system by acting on the myocardial cells or the autonomic nervous system to affect the heart rate, blood pressure or cardiac contractility, directly. Because metabolic abnormalities (especially acidemia, hypotension, hypoxia, and electrolyte abnormalities) can further exacerbate the toxicity, or can be the sole cause of the cardiovascular abnormalities, correction of metabolic abnormalities must be a high priority in the treatment of patients with cardiovascular manifestations of poisoning. The terminal phase of any serious poisoning may include nonspecific hemodynamic abnormalities and cardiac dysrhythmias.
Xenobiotics that directly cause dysrhythmias or cardiac conduction abnormalities usually affect the myocardial cell membrane. These abnormal rhythms, cardiac conduction abnormalities, and heart blocks are discussed in Chapter 22.
Sinus bradycardia is probably the most common xenobiotic-induced bradycardia. Xenobiotics (Table 23–2) produce bradycardia through different mechanisms. The xenobiotic may affect the central or peripheral nervous system, or may affect rhythm generation or conduction in the heart. Most xenobiotics that cause CNS sedation, such as the sedative-hypnotics, opioids, and α2-adrenergic receptor agonist ("centrally acting") antihypertensives, will usually decrease sympathetic outflow to the heart and produce sinus bradycardia in the range of 40–60 beats/min. Digoxin, certain cholinergics, and α1 agonists may produce bradycardia and heart block through the enhancement of vagal tone. Sodium channel activators, such as aconitine, cause bradycardia due to intracellular Na+ overload with a resultant alteration in calcium Ca2+ handling. The most profound bradycardia results from overdoses of xenobiotics that have direct depressant effects on the cardiac pacemakers.54 The ultimate manifestation of pacemaker failure is asystole. Similarly, the inability to propagate an impulse within the cardiac conducting system may produce bradycardia. Examples of xenobiotics that can produce pacemaker or conduction effects include calcium channel blockers and β-adrenergic antagonists.
Table 23–2. Xenobiotics That Cause Bradycardia |Favorite Table|Download (.pdf)
Table 23–2. Xenobiotics That Cause Bradycardia
|α1-Adrenergic agonists (reflex bradycardia)|
|α2-Adrenergic agonists (centrally acting)|
|Calcium channel blockers|
|Carbamates or organic phosphorus compounds|
|Sodium channel openers|
Bradycardia, heart block, and asystole are frequently the terminal events in patients with massive overdose of many noncardiotoxic xenobiotics. These dysrhythmias may occur as a result of direct effects on the myocardial system or of indirect metabolic effects. For instance, severe hyperkalemia or metabolic acidosis results in a wide complex, sinusoidal bradycardic rhythm.
Sinus tachycardia is the most common rhythm disturbance that occurs in poisoned patients. Parasympatholytic drugs, such as atropine, raise the heart rate by elimination of the inhibitory tonic vagal influence. However, more rapid rates require direct myocardial stimulatory effects, generally mediated by β-adrenergic agonism. For example, catecholamine excess (eg, cocaine, psychomotor agitation, methylxanthines, sedative-hypnotic withdrawal) may cause sinus tachycardia with rates faster than 150 beats/min. Tachycardia may also be an indirect effect as occurs in response to hypotension, hypoxia, acidemia, fever electrolyte abnormalities, and other metabolic derangements that may be present in poisoned patients (Table 23–3).
Table 23–3. Xenobiotics That Cause Sinus Tachycardia and Tachydysrhythmias |Favorite Table|Download (.pdf)
Table 23–3. Xenobiotics That Cause Sinus Tachycardia and Tachydysrhythmias
|Botanicals and plants (Chap. 118)|
|Chloroquine and quinine|
|Hydrocarbons and solvents|
|Thyroid hormone preparations|
Decreased Cardiac Contractility and Congestive Heart Failure
Xenobiotics can reduce cardiac contractility with a resulting decrease in cardiac ejection fraction and cardiac output, a decrease in blood pressure, and development of congestive heart failure (CHF). Cardiogenic pulmonary edema generally occurs as a result of the direct effects of the xenobiotic on the contractility, or inotropy, of the heart, or through increases in the preload or afterload. Acute cardiogenic pulmonary edema, resulting from impaired left heart filling (which may be due to decreased cardiac output), occurs in patients poisoned by a non-dihydropyridine calcium channel blocker or β-adrenergic receptor antagonist. Other xenobiotics that can exert direct depressant effects on cardiac contractility include antihistamines, phenothiazines, antidysrhythmics, and local anesthetics. Many of these xenobiotics reduce contractility through sodium channel blockade, which, by slowing intraventricular conduction, reduces the ability of the heart to contract efficiently. Pulmonary edema may also result from the fluid overload accompanying ingestion of large quantities of sodium-containing xenobiotics (eg, sodium penicillin), the renal effects of medications such as NSAIDs, or as a late consequence of xenobiotics that cause renal failure (Chap. 27).
Xenobiotic can cause cardiomyopathy through chronic toxic effects directly on the myocardium or indirectly through effects on blood pressure or cardiac vasculature (Table 23–4). In most cases, the exact mechanism of the toxicity is not known. However, free radical generation, nitric oxide formation, acetaldehyde, myocardial ischemia, mechanical overload, nutritional deficiency, and persistent tachycardia are each implicated in the cellular toxicity of the various xenobiotics and development of cardiomyopathy.
Table 23–4. Xenobiotics Commonly Associated with Cardiomyopathy |Favorite Table|Download (.pdf)
Table 23–4. Xenobiotics Commonly Associated with Cardiomyopathy
|Anthracyclines (dactinomycin, daunorubicin, idarubicin, and doxorubicin),|
|Emetine from syrup of ipecac|
|HMG Co-A reductase inhibitors|
Blood Pressure Abnormalities
Blood pressure is dependent upon cardiac and vascular function. The blood pressure (BP) is directly related to the heart rate (HR), the stroke volume (SV), and the systemic vascular resistance (SVR): BP = HR × SV × SVR. The systolic component of the blood pressure measurement is a reflection of the inotropic state of the myocardium, whereas the diastolic component reflects the vascular tone. It is important to consider both components of the blood pressure. Blood pressure may be expressed also the mean arterial pressure (MAP) during a single cardiac cycle. Since at normal heart rates the duration of diastole is approximately twice that of systole, the MAP is calculated as [(2 × diastolic) + systolic]/3]. Xenobiotics may affect either component and compensatory mechanisms within the cardiovascular system may produce recognizable patterns of blood pressure alterations.
Many xenobiotics affect blood pressure by modulation of normal neurotransmission at the postganglionic sympathetic neurons. Through these effects they may cause, for example, vasoconstriction (α agonism) or inotropy (β1 agonism). Because of the functional similarity of most sympathomimetics, physical examination alone seldom identifies the specific causative xenobiotic in any patient. However, often a clinical constellation of signs and symptoms can be identified that is associated with this general class. For example, patients who ingest sympathomimetic amines such as cocaine or amphetamines typically have central nervous system stimulation, hypertension, and tachycardia (Chap. 3).
Hypertension Caused by Xenobiotics
Hypertension may be the result of an increase in either inotropy or vascular resistance or both. For example, stimulation of the α1-adrenergic receptor causes hypertension through vasoconstriction, and stimulation of the β1-receptor causes hypertension through enhanced myocardial contractility (Table 23–5).
Table 23–5. Xenobiotics That Commonly Cause Hypertension |Favorite Table|Download (.pdf)
Table 23–5. Xenobiotics That Commonly Cause Hypertension
|Hypertensive effects mediated by α-adrenergic receptor interaction||Hypertensive effects not mediated by α-adrenergic receptor interaction|
|Direct α-receptor agonists||β-Adrenergic receptor agonistsb|
|Monoamine oxidase inhibitors|
|Direct- and indirect-acting agonists|
The hemodynamic results of a xenobiotic overdose depend on the specific xenobiotic ingested and the relative action on the various types of receptors (see Table 23–1). This suggests that, among β-adrenergic agonists, only those with a predominant β1 adrenergic effect cause hypertension. Nonselective β-adrenergic agonists (those that agonize at both β1 and β2) produce β1-mediated systolic hypertension (through inotropic effects) with β2-mediated vascular vasodilation and diastolic hypotension. This may result in a widened pulse pressure, which is the numerical difference between the systolic and diastolic pressures. Thus after exposure to selective β agonist (eg, albuterol), tachycardia and enhanced inotropy may occur, resulting in a widened pulse pressure in a manner analagous to a nonselective beta agonist. The resulting blood pressure depends on the relative physiologic balance between inotropy and vasodilation.
Xenobiotics that interact only with the α1-adrenergic receptor (such as phenylephrine) cause vasoconstriction and hypertension. Barorecptors detect the increased blood pressure and signal the parasympathetic nervous system neurons of the vagus nerve to fire and slow the heart rate. In the absence of β-adrenergic stimulation, a "reflex" bradycardia results. Norepinephrine is an α1- adrenergic agonist with additional β-adrenergic activity. Profound hypertension is the primary hemodynamic toxic effect due to the activity of norepinephrine as both a positive inotrope (β1) and a vasoconstrictor (α1). Reflex bradycardia does not occur as a result of stimulation of the cardiac β-adrenergic receptors.
Hypotension Caused by Xenobiotics
Typically, hypotension in adults is arbitrarily defined as a systolic blood pressure of less than 90 mm Hg or a MAP of less than 70 mm Hg. However, this is not an adequate clinical parameter. Young children and adults with a small body habitus may have a normal systolic pressure less than 90 mm Hg (Chap. 3). Patients with hypothermia have decreased metabolic demands, and a lower blood pressure may be considered "normal" for these patients. Most importantly, patients with long-standing hypertension may have inadequate tissue perfusion even with a MAP of more than 70 mm Hg. The cerebral arterioles normally constrict or dilate to maintain a relatively constant cerebrovascular blood flow despite changes in the peripheral blood pressure. Chronically hypertensive patients lose this autoregulatory response as a consequence of atherosclerotic disease, arteriolar hypertrophy, or arteriolar smooth muscle constriction. These narrowed arterioles may require a higher peripheral blood pressure to properly perfuse the brain.
Hypotension is clinically defined as a blood pressure that is inadequate to perfuse tissues. The clinical assessment of tissue perfusion is based on the vital signs, skin color, capillary refill, mental status, urine output and concentration, and acid—base balance (eg, serum lactate concentration). However, if a xenobiotic directly affects one or more of these clinical parameters, the clinical assessment of volume and hemodynamic status may be difficult. Measurement of central venous pressure is beneficial in the early treatment of the sepsis syndrome, and most likely would be beneficial in the treatment of other causes of hypotension, including those occurring in poisoned patients. Invasive measurement of cardiac filling pressure, cardiac output, systemic vascular resistance, and arterial pressures may be necessary in critically ill patients with severe poisoning.46
Poor tissue perfusion may result from hypovolemia, decreased peripheral vascular resistance, myocardial depression, or a dysrhythmia that reduces the cardiac output. A single xenobiotic may exert several effects on the hemodynamic system, such as diltiazem, a calcium channel blocker that causes negative inotropy and vasodilation. Appropriate treatment of the hypotension requires an understanding of the pathophysiologic consequences of the xenobiotic and the resultant hemodynamic derangement (Table 23–6).
Table 23–6. Heart Rate and ECG Abnormalities of Xenobiotics That Cause Hypotension |Favorite Table|Download (.pdf)
Table 23–6. Heart Rate and ECG Abnormalities of Xenobiotics That Cause Hypotension
|Characteristic ECG Abnormalities|
|Heart Rate||Sinus Rhythm||Heart Block or Prolonged Intervals||Dysrhythmia|
|Bradycardia||α2-Adrenergic agonists||β-Adrenergic antagonists||Cardioactive steroids|
|Opioids||Calcium channel blockers||Plant toxins|
|Tachycardia||Angiotensin-converting enzyme inhibitors||Anticholinergics||Antidysrhythmics|
|Arterial vasodilators ||Arsenic ||Arsenic |
|Disulfiram||Cyclic antidepressants||Cyclic antidepressants|
A common etiology of hypotension in a poisoned patient is intravascular volume depletion. Intravascular volume may decrease due to gastrointestinal, urinary, or insensible losses; or fluid may redistribute from the intravascular space into the intracellular, interstitial, pleural, or peritoneal spaces. Xenobiotics can cause significant intravascular volume depletion through all of these mechanisms.
Hypotension may also be caused by xenobiotics that affect the venous tone. These xenobiotics increase venous capacitance, decrease the central venous pressure, and result in a relative hypovolemia. The effects may be mediated via central effects on the sympathetic nervous system or direct effects on the peripheral vasculature. Sedative hypnotics and central α2-adrenergic agonists (eg, clonidine) decrease the central sympathetic outflow and may result in hypotension. Other xenobiotics directly block peripheral α1-adrenergic receptors or stimulate β2-adrenergic receptors on the blood vessels to produce vascular smooth muscle relaxation, venodilation, and hypotension. A large number of xenobiotics are reported to cause hypotension. However, the hypotension often is not a direct action of the xenobiotic. Rather, the cause of hypotension is coexisting hypoxia, acidosis, anaphylaxis, volume depletion, or dysrhythmias.
Identification of the specific xenobiotic causing hypotension requires the integration of a detailed history, complete physical examination, and laboratory studies. Often the identification of the specific xenobiotic responsible for hypotension is based on other physical findings associated with the xenobiotic or recognition of a specific toxic syndrome.