Cyanide Poisoning Case File

https://medical-phd.blogspot.com/2021/03/cyanide-poisoning-case-file.html

Eugene C.Toy, MD, William E. Seifert, Jr., PHD, Henry W. Strobel, PHD, Konrad P. Harms, MD

❖ CASE 16
A 68-year-old female in a hypertensive crisis is being treated in the intensive care unit (ICU) with
intravenous nitroprusside for 48 hours. The patient’s blood pressure was brought back down to
normal levels; however, she was complaining of a burning sensation in her throat and mouth
followed by nausea and vomiting, diaphoresis, agitation, and dyspnea. The nurse noticed a sweet
almond smell in her breath. An arterial blood gas revealed a significant metabolic acidosis. A
serum test suggests a metabolite of nitroprusside, thiocyanate, is at toxic levels.

◆ What is the likely cause of her symptoms?

◆ What is the biochemical mechanism of this problem?

◆ What is the treatment for this condition?

ANSWERS TO CASE 16: CYANIDE POISONING

Summary: A 69-year-old female with new onset burning sensation in mouth and throat, nausea and
vomiting, agitation, and diaphoresis after a medication error was noted. Metabolic acidosis is seen
on the arterial blood gas. A thiocyanate level is in the toxic range.

◆ Diagnosis: Cyanide poisoning from toxic dose of nitroprusside.

◆ Biochemical mechanism: Cyanide inhibits mitochondrial cytochrome oxidase, blocking

electron transport and preventing oxygen utilization. Lactic acidosis results secondary to anaerobic
metabolism.

◆ Treatment: Supportive therapy, gastrointestinal (GI) decontamination, oxygen, and antidotal

therapy with amyl nitrite, sodium nitrite, and sodium thiosulfate.

CLINICAL CORRELATION
Hypertensive emergencies are defined as episodes of severely elevated blood pressure, such as
systolic levels of 220 mm Hg and/or diastolic blood pressures exceeding 120 mm Hg with patient
symptoms of end-organ dysfunction. These symptoms may include severe headache, neurological
deficits, chest pain, or heart failure symptoms. Hypertensive emergencies require immediate
lowering of the blood pressure to lower (but not necessarily to normal) levels. In contrast,
hypertensive urgencies are circumstances of markedly elevated blood pressures in the absence of
patient symptoms; lowering the blood pressure over 24 to 48 hours is reasonable in these cases.
One hazard of abruptly lowering the blood pressure is causing hypotension and subsequent
ischemia to the brain or heart. In other words, the very treatment designed to prevent end-organ
disease may cause the problem. To avoid precipitous hypotension, agents that induce a smooth fall
in blood pressure are preferable, such as sodium nitroprusside, a titratable intravenous agent used
for malignant hypertension. Its desirable properties include the ability to precisely increase or
decrease the infusion to affect the blood pressure. One side effect of sodium nitroprusside is that its
metabolite is thiocyanate, and with prolonged use, cyanide poisoning may result, which inhibits the
electron transport chain. Thus, in clinical practice, short-term nitroprusside is used, or serum
thiocyanate levels are drawn.

APPROACH TO ELECTRON TRANSPORT SYSTEM (ETS) AND CYANIDE

Objectives
1. Know about the function of the electron transport chain (ETC).
2. Understand what factors may inhibit the ETC.
3. Be familiar with the biochemical process by which the therapy for cyanide poisoning works.
(Nitrates convert the hemoglobin to methemoglobin which has a higher affinity for cyanide and
promotes dissociation from cytochrome oxidase. Thiosulfate reacts with cyanide which is slowly
released from cyanomethemoglobin to form thiocyanate. Oxygen reverses the binding of cyanide to
cytochrome oxidase.)
4. Recognize other ETC sites and agents of inhibition.

Definitions
Oxidative phosphorylation: The mitochondrial process whereby electrons from NADH or
reduced flavin bound in enzymes are transferred down the electron transport chain to oxygen
forming water and providing energy through the formation of an hydrogen ion gradient across the
inner mitochondrial membrane. The hydrogen ion gradient is used to drive the formation of ATP
from ADP and inorganic phosphate (Pi). This process is also called coupled oxidative
phosphorylation to emphasize that ATP formation from ADP and P i is coupled to and linked with
electron transport such that inhibition of one also inhibits the other.
Hydrogen ion gradient: A situation developed across the inner mitochondrial membrane wherein
the concentration of hydrogen ions outside the mitochondrion is higher than the concentration
inside. Hydrogen ions are extruded from the mitochondrion by the transfer of electrons from
complex I to coenzyme Q, from coenzyme Q to complex III, and from complex III to complex IV.
The gradient is discharged by ATP synthase, which admits hydrogen ions into the mitochondrion
thereby driving the phosphorylation of ADP by Pi.
Electron transport chain: Present in the mitochondrial membrane, this linear array of redox active
electron carriers consists of NADH dehydrogenase, coenzyme Q, cytochrome c reductase,
cytochrome c, and cytochrome oxidase as well as ancillary iron sulfur proteins. The electron
carriers are arrayed in order of decreasing reduction potential such that the last carrier has the most
positive reduction potential and transfers electrons to oxygen.
Reduction potential: The tendency of an electron carrier to give up electrons, stated in electron
volts, is called reduction potential. In any reduction–oxidation reaction electrons flow from the
species with the more negative reduction potential to the more positive reduction potential.
Cytochrome: A heme (protoporphyrin IX) containing electron transfer protein. Some heme
moieties are covalently attached to the protein components (cytochrome c), whereas others have
isoprenoid side chains (cytochromes a and a 3).
Iron sulfur proteins: These carry one electron and contain centers that chelate iron with organic
and inorganic sulfur. Some centers contain a single iron atom chelated by four cysteine sulfurs;
others contain two iron atoms chelated through four cysteine sulfurs and two inorganic sulfurs; yet
others contain four iron atoms chelated by four cysteine sulfurs and four inorganic sulfurs.
Coenzyme Q (ubiquinone): A two electron accepting quinone that can accept and transfer one
electron at a time allowing it to exist in a semiquinone state as well as the fully oxidized quinone or
fully reduced dihydroxy state. It is bound to multiple isoprenoid units (ubiquinone has ten units),
allowing it to bind to the membrane.
Flavin mononucleotide (FMN): An isoalloxazine ring bound to ribosyl monophosphate in an N-
glycosidic bond. FMN can accept two electrons or donate one at a time to another electron
acceptor.
Flavin adenine dinucleotide (FAD): An isoalloxazine ring bound to ribosyl monophosphate in an
N-glycosidic bond which is attached to adenosine monophosphate. Like FMN, FAD can accept or
donate two electrons one at a time to another electron acceptor.