"cardiotoxicity" can result in 3 different ways to be unhealthy to the heart, which are?
(1) Cardiomyopathy (impaired muscle function) (2) Cardiac arrhythmias (changes in cardiac conduction) (most common one seen with cardiotox) (3) Signiﬁcant changes in blood pressure (pre- and afterload)
Impairing conductance= dysrhythmias. what 5 plants cause this?
digitalis - oleander - azalea - avocado - lily of the valley
what is the substance in the plant that is usually bad for the heart?
what are the things in chocolate that cause toxicity? which us more toxic?
Caffeine, theophylline and theobromine--these are all methylxanthines. Theobromine is more tox than caffeine, and theo also has a longer half life
compare theobromine and caffeine-- also, what is their bioavailability, how are they metabolized, how are they eliminated?
Caffeine and theobromine (methylxanthines) both work on the adenosine receptors. Theobromine is more powerful AND has a longer half life than the caffeine. Both are highly bioavailable, both are metabolized, and undergo enterohepatic circulation. can be eliminated unchanged with urine, or metabolites can be elim with urine or with bile (must be in bile bc there are enterohepatic circulation) however, once put into urine, CAN be reabsorbed from bladder.
what are methylxanthines and receptor do they effect? what are the effects of this receptor?
These are things like caffeine and theobromine- which are in chocolate. They bind to the adenosine receptor (a G-protein coupled receptor) and has an effect on adenylate cyclase, and the usual effects of stimulation of the adenosine A-2-alpha receptor is that you become relaxed and you can go to sleep. And if you antagonize the receptor, you become alert/hyper. Both caffeine and theobromine ANTAGONIZE the adenosine receptor, leading to hyperactivity
aside from their effect on the adenosine receptor, what other effect effect do methylxanthines have on electrolytes? what does this result in?
They also have an effect on Ca++... they inc intracellular Ca++. which would inc the contractility of mm, ESP the heart (And striated mm)
what receptors do methylxanthines compete with (that isnt adenosine)? what does this result in?
they also compete with benzodiazepine receptors, and inhibit phosphodiesterase, and inc epi and norepi concentrations. (so methylxanthines have mult targets-- which is sthing evident when you see the CSs of chocolate ingestion).
common clinical signs of chocolate ingestion? (briefly brainstorm tx for these CSs)
vomiting! (if it's early (2,3,4 hours), let them vomit! let them get it out. Until it has been a while and they are still vomiting, then might want to stop vomiting to stop fluid loss. Think of Maropitant citrate, Metoclopramide) elevated HR is another CS aka arrhythmias (can do a beta-1 blocker like propranolol to slow down heart. if that doesn't work, you can try Ca++ channel blockers or local anesthetics like lidocaine.) Since they atagonize the benzodiazepines, they lead to hyperactivity as a CS. and if hyperactive in brain--> seizures (can try to tx seizures with benzos, high enough dose to overcome block by theobromine-- and if that doesnt work, try phenobarb (barbiturates) ) can consider pushing fluids to cause diuresis to clear theobromine in urine, or put catheter in so that urine doesnt stay in bladder and so it wont be reabsorbed.
what is LD50 of methylxanthines like for cat? dog? (who is it more toxic in)
MORE TOXIC IN CAT BC LOWER LD50 AT 200mg/kg. DOG is 300mg/kg
why is theobromine more of a prob in our pets than in us?
how do macrolides affect the ECG? how about the heart in general? (what other drugs are these effects seen in?)
see ECG changes (QT prolongation), Myocardial damage, and Generates oxidative stress. Also seen with ﬂuoroquinolones and ketolides
Explain how this drug affects the ECG. what are the drugs that do this?
So there are changes in the P wave-- the PQ time is shortened. then there is a longer time between QRS complex and the T wave (measure by the peak). So, Q-T prolongation. The 3 things that do this are the macrolides(like axithromycin), fluoroquinolones(like ciproflox), and ketolides
why is there a Q-T prolongation with these drugs?
bc of interaction with one of the many electron transporters in the cardiac cell-- in this case, a block of the HERG channel. HERG is responsible for xporting K+ out of the cell, and K+ going out of the cell is what causes electrical balance to be re-achieved after all the Na+ goes in hence causing repol. So there is a delay in repolarization--> inc Q-T length. This might result in many things including ventricular tachycardia.
review: what causes depol of cell? repol? how do macrolides effect this?
rapid influx of Na+ (so goes from -90mv to +20mv in pic-- due to inc in intracellular Na+) then see gradual outflow of K+, esp during repol phase--> and what is responsible for this movement of K+ is the HERG channel. And macrolides block that channel. so movement of K+ is delayed, which results in an extended occurance of the T wave.
explain what happens when the HERG channel is blocked
Block the channel, inc action potential duration (longer for repol, earlier depols) which leads to a prolonged QT segment, leading to hear arrhythmias like torsades de points and then degenerating into vfib. (This also explains why these abx are cytostatic, bc they are working on these channels too)
what are the major problems and CSs the macrolides have as a result of their MOA?
Prolongation of cardiac repolarisation and sudden death syndrome--> V-fib. (also why they are cytostatic in the cells they are designed to kill)
COCCIDIOSTATICS ( antiprotozoal agent that acts upon Coccidia parasites) IN ANIMAL FEEDS. Also bonus functions of ionophores are inc growth rate of animals. promote growth and promote feed efficiency. so widely used in extensive farming.
monensin is particularly well known for being toxic in who?
ionophores form cationic complexes-- what does this do?
enhances transport of themselves over membranes
what are ways monensin/ionophores are administered to cattle?
Slow release devices (rumen bolus) or in feed medication
ionophores are antimicrobial against what bact?
how do Carboxylic ionophores increase food utility?
Reduce G+ bacteria. In the RUMEN: Reduction of gram-positive bacteria and acetic acid and butyric acid producing bacteria. Promotion of propionic acid producing gram-negative bacteria-> the combo of these results in better feed utility, as well as help treat ruminal acidosis and ketosis
how does ionophores help tx rumen acidosis?
bc dec G+ bact that make acetic acid and butyric acid
what is the MOA of ionophores (monensin)?
DEPENDS ON THE IONOPHONE
what is the MOA for MONENSIN? (what is the resulting cellular pH?)
REsults in cellular alkalosis because there is an inc in Na+/K+ ATPase-- because Na+ is more readily pumped into the cell, which means K+ and H+ are kicked out-- less H+ in cell, means cell is alkalotic.
what is the MOA of Salimomycin - narasin? (What is the resulting cellular pH?)
They cause a large efflux of K+ out of the cell, which pushed H+ into the cell, resulting in cellular acidosis.
what is the common MOA with monensin and salimomycin/narasin? what are the results of all the changes?
ALL of them inc Ca++ATPase, which causes more Ca++ to go into cell and Na+ to go out.... so leads to huge inc in Ca++ in the cell. So, because of all these changes of electrolytes in the cell, here is an ion imbalance in the cell (Can result in cell death--> cardiotoxicity, esp since they seem to have preference for cardiac cells+mm cells--> sp diff if you see more cardiac vs striated mm signs).
Toxic effects of ionophores on striated muscle cells-- explain the MOA.
there is a large influx of Na+ and efflux of K+. This leads to inc Ca++ influx, Excessive uptake of Ca 2+ by mitochondria, mitochondrial damage, lack of energy, and muscle necrosis (including the myocardium). some of them also cause less Ca++ efflux (meaning net inc in Ca++ in cell). Also inc catecholamine--> influx of Ca++ also. Free radicals can form bc of mm necrosis. The free radicals lead to membrane perturbation (deviation of the system) which causes lipid peroxidation, which we already learned causes oxygen free radicals to be formed--> further damage to the cells.
INC Ca++ uptake results in what?
inc signaling for apoptotic cell death which also accounts for inc mm necrosis
what are the clinical signs you see with ionophore toxi?
In several animal species: anorexia, diarrhoea, depression, hypoactivity/reluctance to move, dyspnea, leg weakness, ataxia and recumbency
how do you tx ionophore tox?
no antidote. Feed change, adherence to species restrictions
what are the histo effects of monensin on horse hearts?
Inﬁltration of neutrophils and lymphocytes in necrotic muscle ﬁbers--- this is bc the ionophores are causing cell death and the neuts are going there to clean up the mess.
what is the lethal dose of monensin in horses?
2.5 mg/kg bw
Histology and lab ﬁndings after a sub-lethal dose in horses?
in monensin tox, who do we mainly see heart lesions in?
in monensin tox, who gets mm lesions most commonly? (in order of affectedness)
sheep > pigs > dogs > cattle > horses
clinical signs of ionophore intoxications
Anorexia, Diarrhea (monensin and lasalocid), Depression, Hypo-activity, Reduced feed conversion, Dyspnea, Leg weakness, Ataxia, recumbency, Growth depression, Drop in egg production
what is monensin tox like in humans?
(ppl take it to try to inc their mm mass) Sickness, nausea, abdominal pain, myoglobinuria, weakness, severe muscle pain, tachycardia, cardiac probs, inc in mm enzymes (CK, LDH, creatinine). Death after 6 days: acute rhabdomyolysis & renal failure
Coccidiostatics in feed: drug-drug interactions--> explain how monensin affects other drugs. What drugs make monensin more toxic? less toxic? and by what mechanism?
Monensin is demethylated by CYP450-3A (in parenthesis he had 1A2, 2E1 also)-- this means that drugs that INHIBIT CPY-3A (like barbiturates, tiamulin, macrolides, fluoroquinolones) will cause a reduced tolerance for monensin (inc effect)---> leading to death in chickens (tiamulin and monensin) and Deaths in pigs (valnemulin and monensin) On the other hand, barbiturates STIM CYP450 so that can enhance elim/breakdown of ionophores/coccidiostatics
digitalis - oleander - azalea - avocado - lily of the valley
what are the most important drugs that lead to cardiac tox?
coccidiostats (monensin, salinomycin, narasin), Macrolides (erythromycin, azithromycin, clarithromycin) (also fluoroquinolones like ciproflox under this heading), methylxanthines (like caffeine and theobromine)
what is the MOA of macrolides?
Blocks HERG channel leading to slower repol (since HERG is responsible for getting K+ out of the cell to cause repol
what are the CSs of ionophore tox in horses?
mitochondral swelling, cellular (myocyte) necrosis, inflammatory reaction due to macrophage invasion, tissue fibrosis leading to chronic heart failure. (histo see Inﬁltration of neutrophils and lymphocytes in necrotic muscle ﬁbers)
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