Cardiovascular Toxicology Flashcards
What 5 aspects of the cardiovascular system make it susceptible to toxicants>?
- high energy requirement
- high level of exposure to toxicants from systemic circulation
- limited protection mechanisms
- limited ability to handle structural loss (injured cardiomyocytes are most commonly replaced by fibrosis)
- wide distribution and high heterogeneity (blood vessels)
What are the direct and indirect mechanisms of cardiac toxicity?
DIRECT - alteration of functional or biochemical properties of the heart by ion homeostasis interference, altered coronary blood flow, altered metabolism, oxidative stress, and altered structure (organelle dysfunction of mitochondria, SR, and myofibrils)
INDIRECT - toxicoses in other body systems, acid -base disturbances, hemodynamic alterations (hypovolemia)
What are the direct and indirect mechanisms of vascular toxicity?
DIRECT - alteration in structure and function, metabolism, and immunological events
INDIRECT - altered endothelial permeability due to changes in hydrostatic and oncotic pressure, impaired hemodynamics due to altered platelets or coagulation factors
What are the 3 manifestations of cardiac dysfunction?
- arrhythmia - disturbances in heart rate (chronotropic), contractility (inotropic), conductivity (dromotropic), excitability (bathmotropic)
- CHF - cardiogenic shock, lung edema (left-sided), peripheral edema (right-sided)
- weakness, collapse, recumbency
What are the 2 manifestations of vascular dysfunction?
- excessive contraction or relaxation of arterioles
- increased capillary permeability
What is the most common source of cardiac glycosides? What species is especially sensitive?
digitalis glycosides, digoxin and digitoxin, derived from the leaves of purple foxglove
male cats achieve higher serum levels of cardiac glycosides
How do the absorption, protein-binding, and elimination of digitoxin and digoxin compare?
DIGITOXIN - rapid and nearly complete absorption, highly protein-bound (low VD), biliary-fecal elimination (longer half-life)
DIGOXIN - variable absorption, low protein-binding (high VD), urine elimination
How does body weight affect cardiac glycoside dosage?
plasma drug levels do not change significantly with body fat - based on lean BW
(CGs have narrow therapeutic index)
What is the mechanism of toxicity of cardiac glycosides?
- inhibit Na/K ATPase, which decreases intracellular K and increases intracellular Na concentrations
- intracellular Na is exchanged for extracellular Ca, increasing its intracellular concentration, which increases cardiac muscle contraction
- decreased intracellular K decreases the resting membrane potential in the pacemakers, allowing vagal (parasympathetic impulses that inhibit heartbeat) tone to predominate
What cardiac signs predominate with cardiac glycoside toxicity? What other signs are seen?
bradycardia, heart block, ventricular tachycardia and fibrillation, hypotension, weakness, depression, recumbency
- nausea, vomiting, diarrhea: stimulate CTZ and irritate gastric mucosa
- dehydration
- hyperkalemia (most significant and consistent alteration in serum chemistry)
What is the antidote for cardiac glycoside toxicity? What symptomatic treatments are recommended?
Digibind
- treat cardiac dysrhythmias: Atropine (bradycardia/increased vagal tone) and Lidocaine (ventricular tachycardia)
- treat hyperkalemia: sodium bicarbonate, glucose + insulin
- IV fluids to maintain perfusion and blood pressure
What are 4 common calcium channel blocking agents? Where are they absorbed? What species are most affected?
- Verapamil
- Diltiazem
- Nifedipine
- Nimodipine
small intestine, with significant first pass effect
cats and dogs - smaller individuals are at higher risk of intoxication form ingestion of owner’s medication
What is the mechanism of toxicity of calcium channel blockers? Where is the effect more evident?
prevents the opening of voltage-gated L-type calcium channels, which inhibits calcium-dependent processes in cardiac and vascular cells
at SA and AV nodes, which depend on calcium currents for excitation
What clinical signs are associated with calcium channel blocker toxicity?
- hypotension
- bradycardia
- peripheral and pulmonary edema
- AV block
- nausea, vomiting
- disorientation, depression
What is recommended for hypotension and refractory hypotension treatment in calcium channel blockers? What is the antidote?
- IV fluids
- Isoproterenol or vasopressor agents, like epinephrine or dopamine
calcium chloride or calcium gluconate
What are some common bronchodilators? What is their mechanism of toxicity?
Albuterol, Isoproterenol, Clenbuterol, Terbutaline
stimulation of β receptors with selective agents losing their specificity and stimulating both β1 and β2 receptors
How does the stimulation of different receptors alter clinical signs of bronchodilator toxicity?
- stimulation of β2 receptors in blood vessel smooth muscle - relaxation, peripheral vasodilation, hypotension, reflex tachycardia
- stimulation of β1 receptors in heart - increased heart rate, increased force of contraction and arrhythmias (angina)
How do methylxanthines cause their cardiac signs? What are the 2 most common CVS signs? What other mechanisms of toxicity do they have?
blockade of adenosine receptors that regulate heart rhythm, lower heart rate, and slow AV conduction —> cardiac arrhythmia and hypotension
- stimulate sympathetic nervous system
- elevates intracellular calcium
- increases cAMP by inhibiting phosphodiesterase
What is the mechanism of toxicity of ionophores? What CVS signs are associated with toxicity?
preferentially transports monovalent cations across cell membranes resulting in ion imbalance and deficits in excitable tissues
- tachycardia
- MM congestion
- hypotension
- recumbency
What is the mechanism of toxicity of cardiotoxic plants? What are 4 examples of such plants?
inhibit Na/K ATPase, which decreases intracellular K and increases intracellular Na concentrations, resulting in a decrease in membrane potential of pacemakers and increased intracellular calcium and muscle contraction
- Foxglove (Digitalis purpurea)
- Oleander (Nerium oleander)
- Lily of the valley (Convallaria majalis)
- Dogbane, Indian hemp (Apocynum spp.)
What is the toxic principle of foxglove? What causes death? Why is poisoning infrequent? What is it a common herbal remedy for?
digitoxin, digoxin, gitoxin - AV-block and ventricular fibrillation
plant is not very palatable
edema and heart disease
What are the 2 main groups of toxic principles in oleander? What causes poisoning in livestock?
- cardiac glycosides: oleandrin, digitoxigenin, gitoxigenin
- strychnine-like toxin: rosagenin
ingestion of clippings or fallen leaves
What is the toxic principle of lily of the valley? What species are susceptible?
cardiac glycosides: convallarin, convallamarin, convallatoxin
livestock, pets
What are the 2 toxic principles of dogbane/Indian hemp? What species are mostly affected?
cymarin and apocynamarin —> digitalis glycoside-like effects
horses, sheep, cattle
What are the possible treatment plans for cardiotoxic plants?
- remove animals from the source
- decontaminate with emesis and activated charcoal
- Digibind
- Atropine: bradycardia, increased vagal tone
- Lidocaine: ventricular tachycardia
- sodium bicarbonate/glucose + insulin: hyperkalemia
- IV fluids: BP, perfusion
What are the main sources of grayanotoxins? Where are the toxins found? What do they cause?
ornamental and natural Ericaceae (heath) family - Rhododendron, Kalmia (laurels), Leucothoe, Pieris, Lyonia —> leaves*, nectar, flowers, stems
toxic honey poisoning
What species are susceptible to grayanotoxin toxicity? In what species is toxicosis most common?
livestock and pets
GOATS in the winter since the plant is able to retain their green leaves
What is the main cause of grayanotoxin toxicity? What kind of absorption is suspected?
ingestion of trimmings
rapid absorption and clearance due to the early appearance and quick disappearance of clinical signs
What is the mechanism of toxicity of grayanotoxins? What 2 things does this cause?
binds to Na channels in cells of excitable tissues, slowing their opening and closing and decreasing their ion selectivity
- increases membrane permeability to Na, causing cells to remain in a state of depolarization
- accumulation of Na intracellularly leading to its exchange with Ca —> increased contraction or release of neurotransmitters
What are the 3 levels of clinical signs of grayanotoxin toxicity? What causes death?
- INITIALLY = GI signs: depression, anorexia, salivation, vomiting, regurgitation, abdonimal pain
- LATER = CVS signs: tachycardia, tachypnea, irregular respiration, lateral recumbency
- SEVERE POISONING = CNS signs: opisthotonus, ataxia, seizures, convulsions, pyrexia
secondary aspiration pneumonia and convulsions (usually non-fatal)
What are the 4 forms of supportive and symptomatic treatment of grayanotoxins?
- IV fluids with sodium bicarbonate and 5% dextrose for hypotension, dehydration, and metabolic acidosis
- Atropine for severe bradycardia
- antiarrhythmics (β-blockers, calcium channel blockers, sodium channel blockers) for severely poisoned animals
- stomach tube, trocar, and cannula to relieve bloat
What is the toxic principle of yews and ground hemlock (Taxus spp.)? What species are most susceptible? Which are resistant?
taxine alkaloids with a complex mixture of cardiotoxins found in leaves, bark, and wood —> toxicatin, taxicin, taxinine, taxusin, taxol
livestock, especially horses
goats
What are the 3 main geographical distributions of yew (Taxus spp.)?
- northern and souther US
- pacific region
- southern Canada
What parts of the yew are toxic?
all parts except arils, the fleshy structure surrounding the seed
What 2 situations are associated with yew exposure?
- disposal of clippings on pastures (proper disposal is by compost or burning)
- livestock gaining access to landscaped lots
What is the mechanism of toxicity of yews?
taxine alkaloids induce fatal cardiac conduction disturbances by:
- causing AV conduction blocks with diastolic cardiac arrest
- negative inotropic and chronotropic actions leading to decreased heart contractility and heart rate
- increasing cytoplasmic calcium concentration by acting as calcium and sodium channel antagonists
What clinical sign is most associated with yew toxicity? What else can occur?
sudden death from acute cardiac failure —> animals collapse suddenly as if shot and die
those that survive exhibit…
- anxiety, depression
- bradycardia
- jugular pulsation, absence of external maxillary artery pulse in horses
- hypothermia
- dyspnea
- muscle tremors, ataxia, convulsions
- collapse, recumbency
What is the recommended treatment for yew toxicosis?
- remove animal from source
- rumenotomy with removal and replacement of contents
- Atropine for depressant effects of taxine
- IV fluids
What 4 conditions do calcinogenic glycosides cause? What is the main source? What species are susceptible?
- calcinosis
- enzootic calcinosis
- Naalehu disease (HI)
- Manchester wasting disease (Jamaica)
members of the Solanaceae family containing calcitriol or calcitriol-like compound (Solanum malacoxylon, Mierembergia veitchii, Cestrum diurnum)
cattle, horses, sheep, goats, pigs
What is the mechanism of toxicity of calcinogenic glycosides? What is the net result?
active form of vitamin D (calcitriol) increases Ca absorption from the GIT and resorption from bone, and decreases renal Ca excretion
hypercalcemia and hyperphosphatemia with calcification of soft tissues if Ca and P > 60 mg/dl
What clinical signs are associated with calcinogenic glycoside toxicity? What causes death?
progressive and early signs go unnoticed
- depression, weakness, weight loss, stunted growth
- infertility
- impaired or stilted gait
- grazing on knees, frequent recumbency
- cardiac arrythmias*
emaciation, weakness, cardiac and pulmonary insufficiency
What are the 3 main treatments for calcinogenic glycoside toxicity?
- remove animal from plant source and give clean feed
- discontinue vitamin D supplements
- if practical (non-herd poisoning), give Furosemide, Prednisolone, saline diuretics, calcitonin, or Pamidronate
