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HY points followed by a quiz at the end
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| Acetaminophen | N-acetylcysteine |
| Acetylcholinesterase inhibitors (e.g., neostigmine) | Atropine |
| Anthracyclines (i.e., doxorubicin, hydroxydaunorubicin) | Dexrazoxane |
| Atropine | Physostigmine |
| Arsenic | Dimercaprol |
| Benzodiazepines (e.g., diazepam) | Flumazenil |
| β-blockers (e.g., propranolol) | Glucagon |
| Carbon monoxide | Hyperbaric oxygen |
| Cisplatin | Chloride diuresis (normal saline); amifostine |
| Copper | Penicillamine |
| Cyanide | Amyl nitrite; hydroxocobalamin; thiosulfate |
| Cyclophosphamide | Mesna; N-acetylcysteine |
| Digoxin | Normalize K+; Anti-Digoxin antibody (immunoglobulin Fab fragment); Mg2+ |
| Ethylene glycol | Fomepizole |
| Heparin | Protamine sulfate |
| Iron | Deferoxamine, deferasirox |
| Lead | Dimercaprol; EDTA; succimer |
| Mercury | Dimercaprol; EDTA; succimer |
| Methanol | Fomepizole > ethanol |
| Methemoglobinemia | Methylene blue; vitamin C |
| Methotrexate | Folinic acid (leucovorin rescue) |
| Organophosphates | Atropine first, then pralidoxime |
| Opioids / heroin | Naloxone |
| Salicylates (i.e., aspirin) | Sodium bicarbonate |
| TCA antidepressants | Sodium bicarbonate |
| Warfarin | Vitamin K; fresh frozen plasma |
| 5-fluorouracil (5-FU) | Thymidine; uridine |
Some concise, HY points regarding the above:
Acetaminophen
- Causes hepatic necrosis due to NAPQI production (a highly toxic metabolite). Hepatic glutathione neutralizes NAPQI.
- USMLE wants you to specifically know the reason N-acetylcysteine works is because it regenerates reduced glutathione in the liver.
- Species with thiol (-SH) groups are in the reduced form and can act as reducing agents (i.e., can act as anti-oxidants).
- Species with disulfide bonds (-S–S-) are in the oxidized form.
- Hepatic glutathione has a thiol (-SH) group. So does N-acetylcysteine. After glutathione neutralizes a toxin, it becomes oxidized and inactive.
- The thiol group on N-acetylcysteine then binds to and frees up the sulfurs on glutathione so that they can once again neutralize toxins.
- This mechanism may sound cumbersome, but it’s HY for USMLE. Probably because N-acetylcysteine is such an important antidote used clinically.
- Activated charcoal can be used in select acute circumstances. There’s a Qbank Q floating around where activated charcoal is the answer over N-acetylcysteine. On the USMLE, however, always choose N-acetylcysteine for acetaminophen.
Acetylcholinesterase inhibitors (e.g., neostigmine)
- Acetylcholinesterase breaks down acetylcholine. Therefore AChE inhibitors increase the amount of acetylcholine in the synaptic cleft able to bind to post-synaptic ACh receptors.
- Atropine, a muscarinic receptor antagonist, can therefore act as an antidote by competitively inhibiting ACh receptors.
Anthracyclines (i.e., doxorubicin, hydroxydaunorubicin)
- Doxorubicin (Adriamycin) used in the treatment of Hodgkin lymphoma; hydroxydaunorubicin used in non-Hodgkin lymphoma).
- Cause free radical formation that can lead to dilated cardiomyopathy.
- Dexrazoxane chelates free radicals.
Atropine
- Would cause “opposite of DUMBBELSS” effects.
- Blocks muscarinic receptors directly.
- AChE inhibitors are used as antidotes because they increase ACh available so that it can outcompete atropine for its own receptor.
Benzodiazepines (e.g., diazepam)
- Cause respiratory depression, leading to normal A-a gradient respiratory acidosis (i.e., arterial oxygen is low because the alveolar oxygen is low; this makes sense, as the patient is hypoventilating).
- Flumazenil is a benzodiazepine receptor antagonist.
- Some resources say it should not be used in those with benzo addiction as it can precipitate seizure, but a 2CK NBME Q has flumazenil as the answer used in the emergency setting in a patient with Hx of benzo prescription.
- In other words, on the USMLE, don’t over-think this question: just choose flumazenil if they ask for the pharmacologic Tx for the respiratory depression in someone taking benzos.
β-blockers (e.g., propranolol)
- An easy way to remember that glucagon is the antidote (if that seems weird) is because β-blockers ↓ cAMP by inhibiting G-α-s G-proteins, whereas glucagon ↑ cAMP.
- “Michael, that G-protein point actually makes it more confusing.” –> “Well that G-protein point is sometimes asked for Step 1 as well.”
Carbon monoxide
- Has a much greater affinity for hemoglobin than oxygen, so the only way to attempt to dislodge it from the hemoglobin is to give 100% hyperbaric oxygen –> maximally saturates any binding sites on hemoglobin not already occupied by CO.
Cisplatin
- Chemotherapeutic agent, often for testicular cancer.
- Can cause “toxic neuropathy” (i.e., chemo-induced neurotoxicity); this is on the Neuro shelf forms for 2CK.
- Chloride diuresis (normal saline) is first-line as the Tx for cisplatin toxicity. Amifostine is used second.
Copper
- Penicillamine used as the copper chelator in Wilson disease.
- Penicillamine can cause drug-induced lupus (anti-histone antibodies).
Cyanide
- One of the Step 1 NBMEs has amyl nitrite as the answer for cyanide toxicity.
- Amyl nitrite and thiosulfate can be used together to free the cyanide that’s bound to hemoglobin –> causes chromaturia (pink/magenta urine).
- Hydroxocobalamin + cyanide –> cyanocobalamin (vitamin B12).
Cyclophosphamide
- Guanine-N7 alkylating agent that is highly toxic. Used classically in non-Hodgkin lymphoma as part of CHOP regimen (Cyclophosphamide, Hydroxydaunorubicin, Oncovin [vincristine], Prednisone).
- Causes hemorrhagic cystitis (hematuria –> red urine) due to bladder toxic metabolite called acrolein.
- Mesna, like glutathione and N-acetylcysteine, has a thiol group. Rarely, if Mesna is not listed as an answer for cyclophosphamide antidote, N-acetylcysteine will be correct.
Digoxin
- Hypokalemia can cause digoxin toxicity (both compete for potassium binding site on Na/K-ATPase pump at the heart, so ↓ K means ↑ digoxin binding). If the patient has a low potassium and has yellow/wavy “Vincent van Gogh” vision, normalizing the potassium is the first answer.
- USMLE will ask which of the following agents’ toxicity is treated with an immunoglobulin, and the answer is digoxin (anti-Digoxin immunoglobulin Fab fragment).
- Quinidine is a type Ia anti-arrhythmic (sodium channel blocker) that can displace digoxin from bilirubin and cause digoxin toxicity (i.e., yellow/wavy “Vincent van Gogh” vision in someone also taking an anti-arrhythmic).
- Magnesium is given after potassium is normalized and anti-Digoxin Fab fragment is administered.
Ethylene glycol (anti-freeze)
- Can cause calcium oxylate urolithiasis and high-anion gap metabolic acidosis (the E in MUDPILES –> Methanol, Uremia, DKA, Phenformin, Iron/INH, Lactic acidosis, Ethylene glycol, Salicylates).
- Fomepizole inhibits alcohol dehydrogenase.
Heparin
- Protamine (sulfate) is positively charged. It binds to the large, acidic, negatively-charged heparin molecule.
Iron
- Deferoxamine and deferasirox are used as iron chelators when the patient has secondary hemochromatosis (i.e., transfusional siderosis from chronic blood tranfusions).
- It is the wrong answer for hereditary hemochromatosis (the AR familial disorder). For the latter, the answer is serial phlebotomy. Students fuck this up all the time.
- 34M + hereditary hemochromatosis. Tx? –> answer = serial phlebotomy.
- 12M + beta-thalassemia major + transfusional siderosis. Tx? –> deferoxamine or deferasirox.
Lead
- If the Q gives you a kid eating paint chips after moving into a new house with his family, that’s frankly too easy.
- Lead can cause microcytic anemia. –> 44M + hunter + cognitive decline over many months + microcytic anemia.
- Weird detail, but chelation is not correct unless serum lead levels are >44 ug/dL.
- Succimer is classically used for kids, whereas dimercaprol and EDTA are for adults, but the USMLE won’t make this distinction. The correct answer will be the only lead chelator listed.
Mercury
- Toxicity seen in hatters (mercury used sometimes to create a sheen on furs).
- Heavy metal like lead, so the same chelators are correct.
Methanol
- Toxicity can present as stomach pain and blindness.
- USMLE wants you to know methanol can be in paint thinner.
- Fomepizole is used for both methanol and ethylene glycol toxicity.
- Ethanol has greater affinity for alcohol dehydrogenase, so Jack Daniels can technically be used as a Tx if in a rural area where fomepizole not available, but if the USMLE lists both, choose fomepizole only (i.e., not even the combo of the two; literally just “fomepizole alone”).
Methemoglobinemia
- Oxygen can only bind to Fe2+ oxygen, not Fe3+ (methemoglobin).
- Methemoglobinemia will present frequently as “brown blood,” or “chocolate blood” on the USMLE.
- Congenital methemoglobinemia is due to deficiency of cytochrome B5 reductase (sounds absurd, but it’s on the USMLE).
- Questions on the antidote are easy –> will give you a patient with chocolate blood and then the answer is simply “IV methylene blue.”
Methotrexate
- Can cause pulmonary fibrosis, hepatotoxicity, and neutropenia (mouth ulcers, sore throat, fever).
- Inhibits dihydrofolate reductase.
- Folinic acid (not folic acid) can be used for toxicity. It is also known as “leucovorin rescue.”
Organophosphates
- Organophosphates act as acetylcholinesterase inhibitors –> cause DUMBBELSS in patient working on fruit farm or who “drank fluid” attempting to commit suicide.
- Atropine blocks muscarinic receptors directly. This is the answer before pralidoxime. If the USMLE Q lists both answers, choose atropine first.
- Pralidoxime regenerates active acetylcholinesterase in patients with organophosphate poisoning.
- Pralidoxime will kick out the phosphate group from the organophosphate that’s bound to and inhibiting the acetylcholinesterase –> regenerates active acetylcholinesterase.
- 20F + working on fruit farm + has constricted pupils + bradycardia + drooling; what’s the Tx for this patient’s condition? –> answer = atropine first, then pralidoxime.
Opioids / heroin
- Cause pinpoint pupils and respiratory depression, leading to normal A-a gradient respiratory acidosis (i.e., arterial oxygen is low because the alveolar oxygen is low; this makes sense, as the patient is hypoventilating).
- Naloxone antagonizes opioid receptors.
Salicylates (aspirin) vs TCAs
- Salicylates (aspirin) are acidic, meaning they have hydroxyl (-OH) groups converted to oxylate (-O–) groups at alkaline pH.
- The kidney does not reabsorb charged species as well as neutral ones, so sodium bicarbonate can increase salicylate excretion by forcing it into the oxalate form.
- USMLE Q will ask why bicarb is Tx for aspirin toxicity; answer = “increased excretion through urinary alkalinization.”
- However this is not the same mechanism for TCAs, despite sodium bicarb also being the antidote.
- TCAs are basic, meaning they have -NH3+ that are converted to -NH2 at alkaline pH, so the kidney actually excretes less when sodium bicarb is given. So why the fuck do we give it then?
- Because TCAs are cardiotoxic and can cause arrhythmia by binding to myocardial sodium channels. So sodium bicarb causes 1) the sodium to outcompete the TCA for its own channel, and 2) the bicarb causes dissociation of the drug from the myocardial sodium channel by making it less charged.
- USMLE Q will ask why bicarb is the Tx for TCA toxicity; answer = “increased dissociation from myocardial sodium channels.”
- “Increased excretion through urinary alkalinization” is the wrong answer for TCAs.
- I group salicyclates (aspirin) and TCAs together here because this distinction is so HY.
Warfarin
- Vitamin K is the answer if the patient is not bleeding or is not going to have surgery right away. That is, vitamin K causes a slow warfarin reversal.
- If the patient is actively bleeding or needs to be rushed to surgery, fresh frozen plasma is the answer.
5-fluorouracil (5-FU)
- Inhibits thymidylate synthase, which catalyzes a methyl-group transfer from dUMP to dTMP.
- Tetrahydrofolate (synthesis inhibited by methotrexate) is required as a cofactor for the thymidylate synthase reaction.
- Folinic acid (leucovorin) is not effective to overcome 5-FU toxicity because 5-FU inhibits the enzyme necessary for the methyl transfer, so even if THF is present in sufficient amounts as a cofactor, the enzyme is still inhibited.
- Uridine can be given as a substrate to help overcome the enzyme deficiency (i.e., just drown out the enzyme with sufficient substrate), or thymidine can be given as the product, where the enzyme is bypassed altogether.
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