Cardio Pharmacology- 3 Flashcards
Answer C
Answer B
Answer D
Answer B
Answer B
Answer C
Answer D
Answer E
Answer D
Answer D
Answer B
Answer H
This patient with blurred vision, fever, altered mental status, flushed skin, and dry mucous membranes has anticholinergic toxicity, likely from encountering jimsonweed (Datura stramonium) while working in his yard. Jimsonweed contains large concentrations of the anticholinergic compounds atropine, scopolamine, and hyoscyamine. These agents competitively inhibit acetylcholine at the muscarinic acetylcholine receptor, leading to the classic toxidrome summarized above. Anticholinergic toxicity can be counteracted by increasing the concentration of acetylcholine in the synaptic cleft. Physostigmine, a cholinesterase inhibitor, increases acetylcholine levels by preventing its degradation by cholinesterase.
(Choice A) Organophosphates are cholinesterase inhibitors that are commonly used as pesticides. Atropine can be used to counteract the effects of excess muscarinic stimulation (eg, increased salivation, miosis, bronchospasm, bradycardia). However, patients remain at risk of paralysis due to nicotinic overactivation, and so also require treatment with pralidoxime, a cholinesterase reactivating agent.
(Choices B and D) Benztropine is a centrally acting anticholinergic medication used for the treatment of idiopathic and drug-induced Parkinson disease. Haloperidol is a neuroleptic drug that blocks dopamine receptors in the central nervous system and is used to treat psychosis. These drugs have anticholinergic effects that would worsen this patient’s symptoms.
(Choice C) Diazepam, a long-acting benzodiazepine, positively modulates GABAA action by increasing the frequency of chloride channel opening. It is used to treat seizures associated with atropine poisoning but does not affect muscarinic cholinergic receptors.
(Choice E) Metoprolol is a selective β1-adrenergic receptor antagonist. It is used to treat angina, acute coronary syndromes, heart failure, hypertension, and arrhythmias.
(Choices F and G) Morphine is an opioid pain medication that exerts its effects by stimulating opioid receptors in the brain. Naloxone is a competitive antagonist of these receptors used for opioid overdose. Morphine has some anticholinergic effects and may worsen symptoms whereas naloxone does not affect cholinergic receptors.
(Choice I) Thiamine (B1) is a cofactor for multiple enzymes used in glucose metabolism. Patients who are chronically deficient (eg, due to alcohol use disorder or malnutrition) can develop Wernicke-Korsakoff syndrome (ataxia, ophthalmoplegia, confusion).
Educational objective:
Anticholinergic agents (eg, atropine, scopolamine) competitively inhibit acetylcholine at the muscarinic acetylcholine receptor. The effects can be memorized with the mnemonic, “Blind as a bat, mad as a hatter, red as a beet, hot as a hare, dry as a bone, full as a flask, and fast as a fiddle,” and can be reversed by cholinesterase inhibitors (physostigmine).
Answer B
Amatoxins are found in a variety of poisonous mushrooms (eg, Amanita phalloides, known as death cap) and are responsible for the majority of mushroom poisoning fatalities worldwide. Ingestion of 1 or more amatoxin-containing mushrooms is a life-threatening emergency. After absorption by the gastrointestinal tract, amatoxins are transported to the liver via the portal circulation where active transport by organic anion transporting polypeptide (OATP) and sodium taurocholate co-transporter (NTCP) concentrates the toxin within the liver cells. There, amatoxins bind to DNA-dependent RNA polymerase type II and halt mRNA synthesis, ultimately resulting in apoptosis. Other organ systems with rapid cellular turnover can also be affected in amatoxin poisoning, including the gastrointestinal tract and proximal convoluted renal tubules.
Symptoms typically start 6-24 hours after ingestion and include abdominal pain, vomiting, and severe, cholera-like diarrhea that may contain blood and mucus. Severe poisoning can lead to acute hepatic and renal failure. Urine testing for α-amanitin can confirm suspected amatoxin poisoning.
(Choice A) Acyclovir and related drugs (eg, famciclovir and valacyclovir) are inhibitors of viral DNA polymerase.
(Choice C) Ricin (from the castor oil plant Ricinus communis) is a potent toxin that inhibits protein synthesis by cleaving the rRNA component of the eukaryotic 60S subunit.
(Choice D) The only function of RNA polymerase I is to transcribe the majority of the eukaryotic ribosomal RNA components. RNA polymerase I is insensitive to amatoxins.
(Choice E) Eukaryotic RNA polymerase III transcribes transfer RNA, 5S ribosomal RNA, and other small RNA molecules. It is only weakly affected by amatoxins.
Educational objective:
Amatoxins are found in a variety of poisonous mushrooms (eg, Amanita phalloides, known as death cap) and are potent inhibitors of RNA polymerase II (halting mRNA synthesis).
Answer D
This patient’s clinical presentation is consistent with cyanide toxicity from nitroprusside. Nitroprusside is a vasodilator with quick onset/offset kinetics commonly used for rapid blood pressure control in patients with hypertensive emergency. Nitroprusside [Na2(CN)5NO] rapidly decomposes to nitric oxide (NO: vasodilator) and cyanide ion (CN−: toxin). Key risk factors for nitroprusside-induced cyanide toxicity include high doses, prolonged infusions, and renal insufficiency (eg, acute kidney injury due to hypertensive emergency).
Cyanide is a potent mitochondrial toxin that binds heme centers in cytochrome c oxidase (complex IV), blocking the electron transport chain. Because mitochondria are unable to reduce oxygen, venous blood returning from tissues remains saturated with oxygen and appears bright red. Loss of aerobic respiration also promotes lactic acidosis. As ATP is depleted, acute cyanide toxicity causes neurologic dysfunction (eg, altered mental status, seizures) and cardiovascular collapse.
Cyanide is cleared by rhodanese, an enzyme that transfers sulfur to cyanide to form thiocyanate (SCN) for excretion in urine. Because cyanide overdose depletes available sulfur donors, one approach to treatment is to provide additional sulfur groups with sodium thiosulfate. Other treatments include hydroxocobalamin (directly sequesters CN−) and sodium nitrite (induces methemoglobinemia to scavenge CN−).
(Choice A) Methemoglobinemia, caused by oxidizing agents (eg, nitrites, chloroquine), and carbon monoxide exposure increase hemoglobin’s affinity for oxygen, which impairs oxygen unloading into the tissues. Both processes disrupt peripheral tissue oxygen delivery, leading to lactic acidosis.
(Choice B) Arsenic inhibits pyruvate dehydrogenase, the rate-limiting enzyme governing conversion of pyruvate to acetyl-CoA for entry into the tricarboxylic acid cycle, causing depletion of ATP. Acute arsenic poisoning presents with severe enteritis (diarrhea) and neurologic dysfunction.
(Choice C) Ethanol is converted to acetaldehyde by alcohol dehydrogenase, with concurrent reduction of NAD+ to NADH. High NADH levels subsequently cause feedback inhibition of lactate dehydrogenase (hepatic gluconeogenesis enzyme), leading to hypoglycemia and lactic acidosis.
(Choice E) Electron transport uncouplers (eg, dinitrophenol [DNP]) cause protons to back-leak across the inner mitochondrial membrane, dissipating the gradient as wasted heat instead of generating ATP. Because they raise the metabolic rate, these agents are occasionally abused as catabolic weight loss agents. Accidental overdose results in fatal hyperthermia.
Educational objective:
Cyanide toxicity is an important adverse effect of nitroprusside. Blockage of mitochondrial electron transport leads to impaired oxygen utilization, causing lactic acidosis, neurologic dysfunction, and cardiovascular collapse.
Answer E
This patient with bradycardia, miosis, diaphoresis, excessive secretions (eg, bronchorrhea, tearing), and weakness with fasciculations has signs of cholinergic toxicity. Most cases of cholinergic toxicity are due to organophosphate pesticides. However, the occurrence in multiple patients in a city setting suggests intentional organophosphate exposure, possibly due to a chemical weapon (eg, sarin, soman).
Organophosphates inhibit acetylcholinesterase in the muscarinic and nicotinic cholinergic synapses, leading to decreased acetylcholine degradation and overstimulation of the corresponding receptors. In addition to widespread increased visceral smooth muscle tone and glandular secretions due to muscarinic hyperactivity (mnemonic: DUMBELS), nicotinic hyperactivity causes muscle weakness and paralysis that can lead to rapid respiratory depression and death.
Initial management of organophosphate toxicity includes atropine, a competitive inhibitor of acetylcholine at the muscarinic receptor, which relieves muscarinic hyperstimulation. However, atropine does not have activity at the nicotinic receptors and cannot treat neuromuscular dysfunction. Therefore, pralidoxime, a cholinesterase-reactivating agent that works at both nicotinic and muscarinic sites, should be administered to any patient with neuromuscular dysfunction (eg, weakness, fasciculations). It should be given only after atropine because pralidoxime can cause transient acetylcholinesterase inhibition, which can momentarily worsen symptoms.
(Choice A) Diphenhydramine is an inverse agonist of the histamine H1 receptor, which allows it to function as an antihistamine. Because the H1 receptor is similar to the muscarinic receptor, diphenhydramine has some antimuscarinic effects (eg, urinary retention). However, it is less potent than atropine, and it would not reverse nicotinic dysfunction (weakness).
(Choice B) Hemodialysis is sometimes used to treat toxic alcohol poisoning, which usually presents with altered mental status, as well as vision changes (methanol) or flank pain and hematuria (ethylene glycol). It is not indicated in cholinergic toxicity.
(Choice C) Hyperbaric oxygen is used to treat severe carbon monoxide poisoning, which presents with nausea, dizziness, and altered mental status. Patients typically have cherry-red cheeks and lips.
(Choice D) Physostigmine is an acetylcholinesterase inhibitor that is sometimes used to treat anticholinergic toxicity (ie, flushing, mydriasis, anhidrosis, fever, urinary retention). It would worsen this patient’s symptoms.
Educational objective:
Organophosphates inhibit acetylcholinesterase, leading to symptoms of muscarinic (mnemonic: DUMBELS) and nicotinic (neuromuscular dysfunction) cholinergic hyperstimulation. Management includes atropine, a competitive inhibitor of acetylcholine at the muscarinic receptor (reverses muscarinic symptoms), followed by pralidoxime, a cholinesterase-reactivating agent that treats both nicotinic and muscarinic symptoms.
Answer D
Muscarine, a toxin found in certain mushrooms, acts as a muscarinic (M) agonist in place of acetylcholine, resulting in an increase in parasympathetic nervous system activity. The M2 and M3 subtype receptors are responsible for most of the toxicities seen in patients.
Although the walls of peripheral blood vessels lack cholinergic innervation, M3 receptors are present on the endothelial surface. Activation of M3 receptors promotes synthesis of nitric oxide (NO), an endothelium-derived relaxing factor. NO diffuses into vascular smooth muscle cells, activating guanylate cyclase and increasing intracellular cyclic-GMP. Increased levels of cyclic-GMP activate myosin light chain phosphatase, which dephosphorylates myosin and prevents interaction of the myosin head with actin, resulting in smooth muscle relaxation and vasodilation. Vasodilation results in hypotension, with persistently low blood pressure leading to somnolence due to inadequate cerebral perfusion.
In contrast, activation of M3 receptors in other sites leads to a G-protein-coupled increase in intracellular calcium, resulting in smooth muscle contraction. Clinically, this contraction manifests as detrusor bladder muscle contraction (Choice A), pupillary constriction or miosis (Choice E), and exocrine gland secretion (eg, salivation) (Choice F).
(Choice B) M2 receptors are predominantly found in cardiac muscle. Activation of M2 receptors leads to a G-protein-coupled decrease in intracellular cyclic-AMP and opens potassium channels to slow depolarization. This combination results in decreased inotropy (less contractility) and chronotropy (decreased heart rate).
(Choice C) Juxtaglomerular cells in the kidney release renin in response to decreased renal perfusion pressure. A muscarinic agonist would not have a direct effect on renin release, although the peripheral vasodilation and bradycardia might indirectly lead to renin release.
Educational objective:
Activation of muscarinic receptors by acetylcholine or cholinergic agonists results in peripheral vasodilation due to synthesis of nitric oxide in endothelial cells, which leads to vascular smooth muscle relaxation (eg, hypotension). Muscarinic receptor activation in other sites causes smooth muscle contraction.
Answer F
This patient’s new-onset seizure, signs of anticholinergic toxicity (ie, dilated pupils, hyperthermia, tachycardia, decreased bowel sounds, urinary retention), and QRS widening are most likely due to tricyclic antidepressant (TCA) overdose. Although newer classes of antidepressants (eg, selective serotonin reuptake inhibitors) are commonly used as first-line therapy, TCAs continue to have a role in the treatment of major depression.
TCAs have an inhibitory effect on multiple receptor types, thereby causing a variety of symptoms in the case of overdose:
Inhibiton of central nervous system receptors can cause sedation (histamine [H1] receptors), seizures (GABA A receptors), and agitation or delirium (central muscarinic acetylcholine receptors).
Antagonism of central and peripheral muscarinic acetylcholine receptors results in anticholinergic symptoms, including hyperthermia, dry and flushed skin, dilated pupils, tachycardia, decreased bowel sounds, and urinary retention.
Cardiovascular toxicity may lead to QRS widening, with increased risk for ventricular arrhythmia due to inhibition of cardiac fast sodium channels. Hypotension can also occur due to blockade of alpha-1 adrenergic receptors.
Cardiovascular toxicity is the major cause of mortality in TCA overdose.
(Choice A) Symptoms of benzodiazepine withdrawal include seizures and tachycardia. Psychosis, tremors, sweating, and anxiety are also common. QRS widening, hypotension, and anticholinergic symptoms would not be expected.
(Choice B) Cocaine overdose has sympathomimetic characteristics that can cause seizures, hyperthermia, and tachycardia, as well as myocardial infarctions and cardiac arrhythmias. However, hypertension (vs hypotension) and diaphoresis (vs dry skin) are expected in a cocaine overdose.
(Choice C) Opioid withdrawal is associated with dilated pupils, mild hyperthermia, and hypertension (not hypotension) but would not cause seizures or cardiac conduction delay. Diarrhea and cramps, as opposed to decreased bowel sounds, are also common in opioid withdrawal.
(Choice D) Salicylate toxicity can present with hyperthermia, altered mental status, and seizures (due to neuroglycopenia). Tachypnea, tinnitus, and acid-base abnormalities are also common. QRS widening, urinary retention, dilated pupils, and decreased bowel sounds are typically not present.
(Choice E) Serotonin syndrome can occur with an overdose of serotonergic antidepressants or interaction between serotonergic medications. It can typically cause hyperthermia and tachycardia but also often presents with agitation, diaphoresis (vs dry skin), hypertension (vs hypotension), and neuromuscular hyperactivity (eg, hyperreflexia, clonus); it is not generally associated with QRS widening.
Educational objective:
Symptoms of tricyclic antidepressant overdose include seizures, anticholinergic toxicity, hypotension, and cardiac toxicity (eg, QRS widening, ventricular arrhythmias).
Answer C
Most available rodenticides contain brodifacoum (“superwarfarin”), a long-acting 4-hydroxycoumarin derivative. By ingesting rodenticide, this patient depleted her vitamin K-dependent clotting factors, thereby causing an acquired coagulopathy (similar to warfarin toxicity) that led to bleeding (gastrointestinal hemorrhage with hematemesis and guaiac-positive stools, ecchymoses). The anticoagulant effect is generally seen approximately 48 hours following ingestion, which represents the time required for depletion of the coagulation factors.
To treat life-threatening bleeding in the setting of coumarin or warfarin toxicity, rapid replenishment of clotting factors II, VII, IX, and X is generally performed through intravenous administration of fresh frozen plasma (FFP), which contains all coagulation factors and other proteins present in the original unit of blood. Additional vitamin K should also be given. Vitamin K alone can be used in patients with abnormal coagulation tests (eg, prolonged prothrombin or partial thromboplastin times) but no bleeding.
(Choice A) Cryoprecipitate (precipitate obtained from FFP by centrifugation/thawing) contains factor VIII, factor XIII, von Willebrand factor, and fibrinogen. Therefore, it would not be of significant benefit when vitamin K-dependent clotting factors (II, VII, IX, and X) require replenishment.
(Choice B) Desmopressin increases plasma levels of von Willebrand factor and factor VIII; it is used in management of hemophilia A and von Willebrand disease.
(Choice D) Rat poison or warfarin does not affect platelet count.
(Choice E) Protamine sulfate is used to treat heparin overdose. It binds to heparin, forming a complex that has no anticoagulant activity.
Educational objective:
Most available rodenticides contain brodifacoum, a long-acting 4-hydroxycoumarin derivative. A patient who has ingested a quantity of rodenticide sufficient to cause coagulopathy and abnormal bleeding (similar to warfarin toxicity) requires immediate treatment with fresh frozen plasma in addition to vitamin K.
Answer A
This patient exhibits signs and symptoms of anticholinergic toxicity, which results from the inhibition of cholinergic neurotransmission at muscarinic receptors. Classic manifestations include fever, delirium, mucosal and axillary dryness, cutaneous flushing, nonreactive mydriasis, and urinary retention. Tachycardia and decreased bowel sounds are other common signs.
Anticholinergic toxicity is associated with numerous over-the-counter (eg, antihistamines, sleep aids, cold preparations) and prescription medications. Tricyclic antidepressants (TCAs) are commonly implicated, particularly ones with strong anticholinergic properties such as amitriptyline. When taken in excess, TCAs can also increase QRS duration, cause arrhythmias, and precipitate seizures.
(Choice B) Typical symptoms of benzodiazepine overdose include sedation, anterograde amnesia, and respiratory depression.
(Choice C) Haloperidol is a high-potency, first-generation antipsychotic (FGA) that primarily causes neurological side effects due to potent D2 antagonism; anticholinergic effects are more common with low-potency FGAs (eg, chlorpromazine).
(Choice D) Prazosin is an alpha-1 adrenergic blocker used to treat hypertension and urinary retention due to benign prostatic hyperplasia. Its major adverse effect is hypotension (especially postural hypotension).
(Choice E) Adverse effects associated with an overdose of a nonselective beta adrenergic blocker include bronchoconstriction, hypotension, and bradyarrhythmias.
(Choice F) An overdose of a selective serotonin reuptake inhibitor (eg, sertraline) may result in serotonin syndrome, which is characterized by agitated delirium, autonomic instability, seizures, myoclonus, hyperreflexia, and diaphoresis (not anhidrosis as in anticholinergic overdose).
Educational objective:
Anticholinergic toxicity is characterized by fever; confusion; cutaneous flushing; dry oral mucosa; and dilated, poorly reactive pupils. Tricyclic antidepressants, particularly amitriptyline, have strong anticholinergic effects.
Answer A
This patient developed bradycardia, tachypnea, and excessive salivation after being exposed to a pesticide, suggesting acute organophosphate toxicity. Organophosphates are acetylcholinesterase inhibitors that produce signs of cholinergic excess due to hyperstimulation of the muscarinic (mnemonic: DUMBELS—see table) and nicotinic (ie, muscle weakness, fasciculations, paralysis) receptors. Most exposures occur with commercial pesticides, typically in farmers/field workers or in children with access to stored chemicals.
Initial management of organophosphate toxicity includes the administration of atropine, a competitive inhibitor of acetylcholine at the muscarinic receptor, which leads to the resolution of muscarinic symptoms (eg, bradycardia, salivation). Patients who exhibit signs of nicotinic hyperstimulation (eg, weakness) should then receive pralidoxime, a cholinesterase-reactivating agent that treats both the muscarinic and nicotinic effects of organophosphates. However, pralidoxime should be given only after atropine because it can cause transient acetylcholinesterase inhibition, which can momentarily worsen symptoms (Choice E).
(Choice B) Flumazenil is indicated to treat benzodiazepine overdose, which presents with sedation but would not be expected to cause bradycardia, tachypnea, or hypersalivation.
(Choice C) Naloxone is indicated for treatment of opioid intoxication, which can cause sedation and miosis but suppresses (not increases) the respiratory rate. Opioid intoxication usually occurs via injection or ingestion, rather than external contact with aerosolized agents.
(Choice D) Neostigmine is another acetylcholinesterase inhibitor that is sometimes used to treat myasthenia gravis; its use would worsen this patient’s cholinergic symptoms.
(Choice F) Sodium bicarbonate is indicated to treat patients with tricyclic antidepressant (TCA) overdose who are at risk for ventricular arrhythmias. However, TCA poisoning presents with altered mental status and anticholinergic signs (ie, flushed skin, mydriasis).
Educational objective:
Organophosphates are acetylcholinesterase inhibitors that are commonly used as agricultural pesticides. Toxicity is characterized by signs of cholinergic excess (eg, miosis, bronchospasm, muscle fasciculations/weakness, diarrhea, vomiting, lacrimation). First-line therapy is atropine, a competitive inhibitor of acetylcholine at the muscarinic receptor.
