Episode 46: Learn all about bronchopulmonary dysplasia’s pathophysiology, tylenol overdoses and treatment, and hydroxyl free radicals.

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Free Radicals

The liver’s brownish pigment is lipofuscin (seen on gross pic; can also be hemosiderin, bilirubin, etc; therefore need to have a case with the gross pic); end products of free radical damage are lipofuscin b/c certain things are not digestible (include lipids).

A. Definition of free radical

A compound with unpaired electron that is out of orbit, therefore it’s very unstable and it will damage things.

B. Types of Free Radicals:

1. Oxygen:

We are breathing O2, and O2 can give free radicals. If give a person 50% O2 for a period of time, will get superoxide free radicals, which lead to reperfusion injury, esp after giving tPA when trying to rid a damaged thrombus. Oxygentated blood goes back into the damaged cardiac muscle=reperfusion injury. Kids with resp distress syndrome can get free radical injury and go blind b/c they destroy the retina – called retinopathy prematurity; also leads to bronchopulmonary dysplasia, which leads to damage in the lungs and a crippling lung disease.

2. Hydroxyl Free Radicals

Water in tissues converted to hydroxyl free radicals, leading to mutations in tissues.Complication of radiation therapy is CANCER (MC cancer from radiation is leukemia, due to hydroxyl free radicals). Fe2+ produces hydroxyl free radicals b/c of the Fenton rxn. This is what makes Fe overload diseases so dangerous, b/c wherever Fe is overloaded, leads to hydroxyl free radicals which will damage that tissue (therefore, in liver leads to cirrhosis, in heart leads to restrictive cardiomyopathy, in pancreas leads to failure, and malabsorption, along with diabetes).

3. Tylenol (aka acetaminophen):

MCC drug induced fulminant hepatitis b/c free radicals (esp targets the liver, but also targets the kidneys). Cytochrome P450 in liver metabolizes drugs, and can change drugs into free radicals. Drugs are often changed in the liver to the active metabolite – ie phenytoin. Where in the liver does acetaminophen toxicity manifest itself? – right around central vein.

Treatment: n-acetylcysteine; how? Well, the free radicals can be neutralized. Superoxide free radicals can be neutralized with supraoxide dismutase (SOD). Glutathione is the end product of the hexose/pentose phosphate shunt and this shunt also generates NADPH. Main function is to neutralize free radicals (esp drug free radicals, and free radicals derived from peroxide). Glutathione gets used up in neutralizing the acetaminophen free radicals.

Therefore, when give n-acetylcysteine (aka mucamist); you are replenishing glutathione, therefore giving substrate to make more glutathione, so you can keep up with neutralizing acetaminophen free radicals. (like methotrexate, and leukoverin rescue – using up too much folate, leukoverin supplies the substrate to make DNA, folate reductase).

4. Carbon tetrachloride:

CCl4 can be converted to a free radical in the liver (CCl3) in the liver, and a free radical can be formed out of that (seen in dry cleaning industry).

c. Effect of NSAIDS on the Kidney

Aspirin + Tylenol = very bad for kidney (takes a long time for damage to be seen). Free radicals from acetaminophen are destroying the renal medulla *only receives 10% of the blood supply-relatively hypoxic) and renal tubules. Aspirin is knocking off the vasodilator PGE2, which is made in the afferent arteriole. Therefore Angiotensin II (a vasoconstrictor) is left in charge of renal blood flow at the efferent arteriole. Either sloughing of medulla or destroyed ability to concentrate/dilute your urine, which is called analgesic nephropathy (due mainly to acetaminophen).

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