Cardiovascular and muscoskeletal toxicology Flashcards
Physiological and chemical biomarkers
HR, BP, ECG, echocardiogram (ultrasound), cardiovascular challenges (E.g., BP changes when lying -> standing), and indirect measures of vascular stiffness
Troponin-1 is specific to cardiac tissue
endothelia-1 is a potent vasoconstrictor selective to blood vessels
ANP released by the atria, increases renal excretion of Na. indicates heart failure or coronary artery disease.
lactate dehydrogenase (where LDH1 > LDH2) indicates heart attack
creatine kinase is released in response to muscular damage
myoglobin released in muscle damage/wasting
rhabdomyolysis overview and causes
when myoglobin is released into the blood following muscle damage. can cause acute kidney injury when excessive myoglobin present.
Caused by hemlock, tubocurarine, and statins
QT prolongation and torsades de pointes overview and mechanism
an extended interval between cardiac contraction and relaxation, increasing risk of abnormal rhythms and cardiac arrest.
Can be genetic or drug induced, identified by an ECG.
Can occur through an increase in current through Na and Ca channels, or a decrease in outwardly rectifying potassium channels or Ikr channel (extends depolarisation)
Torsades de pointes is a complication of long QT syndrome. A life threatening irregular heart beat that can cause sudden raining, palpitations, etc… can degenerate to ventricular fibrillation
examples of drugs that cause QT-prolongation
Terfenadine a prodrug for the antihistimine fexofenadine is a potent K+ channel blocker that causes QT prolongation. incomplete first pass metabolism of terfenadine leads to effects.
Cisapride is a 5-HT4 agonist to increase ACh release - caused children deaths.
Thioridazine, an antipsychotic, that was withdrawn. Haloperidol also increases risk
MDMA, amitryptaline, erythromycin, methadone and quinidine also increase risk.
Treatments for QT-prolongation
Betablockers, pacemaker, IV magnesium sulphate (for torsades de pointes)
If serum [K+] or [Mg2+] is low they should be administered
Doxorubicin cardiotoxicity mechanism and treatment
Treated by dexrazoxane which chelates iron, preventing the formation of doxorubicin-iron complexes.
Doxorubicin (for cancer) causes ferroptosis, oxidative stress, and apoptosis. oxidative agent (through redox cycling with iron) and inhibits topoisomerase II
Acrolein toxicity mechanism and sources of acrolein
Allylamine auses endothelial toxicity. Atherogenic - atherosclerosis
Toxicity occurs in vasculature as allyamine is metabolised into acrolein by SSAO (vascular specific enzyme). Causes sub-endocardial necrosis and vasospasm. also induces vascular SM proliferation.
Cyclophosphamide causes acute cardio toxic effects - endothelial and myocyte damage.
mediated by acrolein produced as a metabolite of it.
Acrolein is also produced in small amounts endogenously via MPO-mediated oxidation of threonine.
Tubocurare toxicity mechanism
Found in south american climbing vine - arrow poison.
Can be used as an arrow poison for hunting due to the low oral bioavailability.
historically used as a muscle relaxant at lower doses, causing minimal negative effects on heart.
Acts by antagonising the nAChRs at NMJs in a non-depolarising and competitive manner.
Hemlock poisoning mechanisms
Contains coniine, which produces biphasic nicotine-like effects.
Can cause rhabdomyolysis and convulsant action on CNS.
Toxicity often occurs via renal failure from rhabdomyolysis
Nicotin toxicity mechanism
nAChR agonist in periphery and CNS. high doses cause neuromuscular blockade, respiratory paralysis - death by asphyxia
Wolfsbane toxicity mechanism
contains aconite. Has anti-inflammatory, analgesic, and anti-rheumatic effects.
It is highly toxic to heart and nerves, causing CNS and respiratory depression, seizures, and cardiac symptoms: palpitations, tachyarrhythmias, fibrillations.
Acts by blocking the inactivation of VGSCs - sustained sodium influx. also blocks hERG (KCNH2) and nAChR - further contributing to toxicity.
Lidocaine, amiodarone, and magnesium can help slightly in treating toxicity.
Ergot toxicity
caused by ergot fungus infecting rye.
Consumption causes potent vasoconstriction (a1-AR mediated) - gangrene. Can also cause hallucinations and convulsions.
