Environmental Path 3

Question 1

Let’s talk about the metabolism of alcohol

Answer 1

1. Stomach/SI - Absorb ethanol without altering it
2. Distributed to all tissues in blood
   2a. Oxidized in blood by: alcohol dehydrogenase, catalase, and microsomal ethanol-oxidizing system
   2b. AD = cytosol of hepatocytes
   2c. MEOS = During high alcohol consumption
   2d. Catalase = minor importance, only 5% of ethanol in liver (uses hydrogen peroxide)
3. Acetaldehyde made by metabolism, converted to acetate by acetaldehyde dehydrogenase, acetate used in mitochondrial respiratory chain
4. 10% excreted unaltered in sweat, breath, urine

Question 2

Let’s talk about how the sx of alcohol change depending on how much you have.

Answer 2

1. 80 mg/dL (3 beers, 15 ounces wine, 4-5 ounces 80 proof liquor) = Drunk driving
2. 200 mg/dL = Drowsiness
3. 300 mg/dL = Stupor
4. > 300 mg/dL = Respiratory arrest/coma eventually
5. 700 mg/dL = Limit chronic alcoholics can tolerate due to 5-10x increase in CYP induction

Question 3

What are the toxic metabolites in alcohol? Just list them now, more detail in next cards

Answer 3

1. Acetaldehyde
2. Decreased NAD
3. ROS
4. Endotoxin

Question 4

Acetaldehyde. Tell more more.

Answer 4

Source: Ethanol oxidation
Sx: Flushing, Nausea, Tachycardia, Hyperventilation
Genetics: Acetaldehyde is high if acetaldehyde DH enzymes are low
Asians = ALDH22 instead of 21 = inactive form of enzyme = High Acetaldehyde

Question 5

Decreased NAD. DO TELL ME MORE PLEASE

Answer 5

Source: AD reduces NAD to NADH. NAD needed for fatty oxidation and conversion of lactate to pyruvate. Leads to fatty accumulation in the liver and lactic acidosis (high lactate and fat)

Question 6

Where are all these ROS coming from?

Answer 6

Source: CYP2E1 of ethanol makes ROS = lipid peroxidation in hepatocyte membranes

Question 7

What’s this endotoxin you speak of?

Answer 7

Source: Alcohol hits gram negatives in gut causing release of LPS endotoxin to stimulate TNF and other cytokines from macrophages and kupffer cells leading to hepatic injury

Question 8

What are we saying the effects of acute alcoholism are?

Answer 8

Fatty change: Accumulation of fat in hepatocytes
GI: Gastritis and ulcers
CNS: Depressed then stimulated = Disordered intellect and motor behavior. Eventually depressed again at cortical and medullary centers including those for respiration

Question 9

What about that chronic alcoholism? More is better eh?

Answer 9

Ha, no.
Liver: Hepatitis, cirrhosis → Portal HTN and incr. risk of hepatocellular carcinoma

GI: Massive bleeding from ulcers or esophageal varices (associated with cirrhosis)

B1 Deficiency (Thiamine): Causes peripheral neuropathies and Wernicke Korsakoff syndrome. Eventually cerebral atrophy, cerebellar degeneration, optic neuropathy

CV: Dilated cardiomyopathy, HTN, decreased HDL → Increased chance of CAD

Endocrine: Pancreatitis (acute + chronic)

Pregnancy: FAS → Microcephaly, growth retardation, facial abnormalities, reduced mental function. Avoid alcohol in first trimester

Cancer: Acetaldehyde-DNA adducts or ALDH2*2 alleles (esophageal CA) → Oral, esophageal, liver, breast (females)

Nutrition: Alcohol = energy = empty calories = nutritional deficiencies

Question 10

So no more alcohol for us ever again in the rest of our lives??? WAHHHHH

Answer 10

Nope, you just need to pick the right stuff:

250 mL of wine per day = Good

1. Increased HDL
2. Reduced platelet aggregation
3. Lower fibrinogen levels

AW YEAH

Question 11

Normal dosing for Acetaminophen

Answer 11

Normal dose = 0.5 g

Overdose = 15-25 g

Question 12

Discuss the metabolism of acetaminophen?

Answer 12

95% detoxified in liver by phase II enzymes → excreted in urine as glucuronate or sulfate conjugates.

5% by CYP2E, producing NAPQI, a toxic metabolite. NAPQI usually gets conjugated with Glutathione. If gluthione is depleted (chronic alcholism) NAPQI accumulates and damages hepatocytes → centrilobular necrosis → liver failure

Question 13

So what’s this NAPQI you speak of? Why is it so bad?

Answer 13

Covalent bonding to hepatic proteins → damage to cell membranes and mitochondrial dysfunction

Depletion of glutathione (GSH) → Hepatocytes more prone to damage by ROS

Question 14

What are the sx of acetaminophen overdose?

Answer 14

1. N/V/D
2. Shock
3. Jaundice
4. Liver failure

Question 15

Tx of acetaminophen overdose?

Answer 15

Within 12 hours = N-Acetylcysteine = Restores GSH levels.

Liver centriolobular necrosis = Liver Transplant

Question 16

Discuss the pathophys involved with aspirin toxicity?

Answer 16

Stimulation of Respiratory System in Medulla → Alkalosis → Metabolic Acidosis → Pyruvate and lactic acid accumulation due to uncoupling of oxidative phosphorylation and Krebs Cycle inhibition. This metabolic acidosis enhances formation of non-ionized forms of salicylates which diffuse into the brain → Anything from nausea to coma

Question 17

What are the sx associated with aspirin toxicity? (defined as 3g+/day

Answer 17

CNS: Headaches, dizziness, tinnitus, hearing impairment, confusion, drowsiness, seizures, coma

GI: N/V/D, erosive gastritis → bleeding and ulcers

CV: Acetylation of platelet cyclooxygenase and irreversible block of Thromboxane A2 production (needed for platelet aggregation → Excessive bleeding → Petechial hemorrhages of skin and internal viscera

Question 18

What can happen with you’re doubling up on aspirin and acetaminophen

Answer 18

Taken chronically → Tubulointerstitial nephritis with renal papillary necrosis (analgesic nephropathy)

Question 19

Cocaine. Talk about the composition and types of this drug.

Answer 19

Extracted from coca leaves → water soluble powder.

Mixed with Talcum powder or lactose. Snort or dissolve in water and inject.

Crack = crystallized cocaine → Heat (causes it to crackle hence the name) and inhale vapors → far more potent than cocaine but same effects

Question 20

Addiction with cocaine?

Answer 20

Psychological addiction, NOT physical. Withdrawal is profound.

Question 21

CV sx associated with cociane?

Answer 21

1. Sympathomimetic, blocks reuptake of Epi and NE and stimulates release of NE presynaptically → Tachycardia, HTN, peripheral vasoconstriction.
2. Enhances platelet aggregation and thrombus formation → Coronary artery vasoconstriction → Myocardial ischemia.
3. Enhanced sympathomimetic activity + ion transport disruption (Na+, K+, Ca2+) → Lethal arrhythmias
4. Development of dilated cardiomyopathy (doesn’t say why)

Question 22

CNS effects of cocaine?

Answer 22

Blocks reuptake of Dopamine → euphoria and hyperpyrexia (very high fever due to dopaminergic pathways of body temperature control) and seizures

Question 23

What about cocaine during pregnancy?

Answer 23

Decreases in blood flow to placenta → Fetal hypoxia, degeneration of neural development and potentially spontaneous abortion

Question 24

What lab will be + for a cocaine user

Answer 24

(+) BE (benzoylecgonine)

Question 25

What's the deal with heroin? Where does it come from?

Answer 25

Poppy plant, closely related to morphine. Cut with Talc or quinine. Administered intravenously or subQ

Question 26

CNS effects of heroine?

Answer 26

Euphoria, hallucinations, somnolence, sedation

Question 27

Can you get sudden death from heroin?

Answer 27

Yes, 1. Profound respiratory depression 2. Arrhythmia 3. Cardiac arrest 4. Severe pulmonary edema

Question 28

What are the effects of cocaine in the lungs?

Answer 28

Edema, septic embolism (from endocarditis) lung abscess, foreign body granulomas from Talc, opportunistic infections. Note, granulomas can be found elsewhere like spleen, liver and lymph nodes Imaging: Talc crystals under polarized light, sometimes in giant cells

Question 29

What kind infections are common with heroin use?

Answer 29

1. Right sided tricuspid - S. Aureus 2. Viral hepatitis: most common infection 3. HIV due to needle sharing

Question 30

What skin shit happens with heroin use?

Answer 30

Cutaneous lesions from subQ injections, hyperpigmentation over injection sites

Question 31

Kidney stuff with heroin?

Answer 31

1. Amyloidosis from skin infections 2. Segmental glomerulosclerosis. 3. Proteinuria 4. Nephrotic syndrome

Question 32

What lab will you see with heroin use?

Answer 32

6-MAM (monoacetylmorphine)

Question 33

How do you treat a heroin overdose?

Answer 33

methadone therapy

Question 34

What bad things do burns cause?

Answer 34

1. Shock: Shift of body fluids into interstitial compartment 2. Pulmonary and generalized edema→ Vascular leakiness 3. Hypermetabolic state→ heat loss and need from nutritional support. 4. Infection→ most common organism=*Pseudomonas aeruginosa, MRSA, Candida. 5. Airway and lung injury from inhalation → complete or partial airway obstruction

Question 35

Classification of burns

Answer 35

1* Superficial: confined to epidermis, 2* Partial thickness burns: injury to top of dermis, wet and pink Deep partial thickness: through all dermis, dry and red 3* Full-thickness: extension to subcutaneous tissue, white/brown and leathery, no pain 4* into muscle tissue or bone, black charred

Question 36

What kind of injuries do we see in hyperthermia

Answer 36

1. Heat cramps: from loss of electrolytes from sweating. A/w vigorous exercise 2. Heat exhaustion: most common. From failure of cardiovascular system to compensate for hypovolemia caused by dehydration. Onset is sudden with prostration and collapse 3. Heat stroke: A/w high temp, high humidity and exertion. At risk: older people, people undergoing physical stress, people with CV dz.

Question 37

More on heat stroke. What is the pathophys involved here

Answer 37

1. Body temp>40C→ multiorgan dysfunction. 2. Generalized vasodilation→ peripheral blood pooling and ineffective circulation. 3. Sustained contractions of skeletal muscle contractions→ muscle necrosis and rhabdo.

Question 38

Why are there sustained muscle contractions seen in heat stroke?

Answer 38

RYR1 nitrosylation disruption: RYR1 is responsible for regulating Ca2+ release in sarcoplasm in skeletal muscle. Heat stroke causes RYR1 dysfunction allowing Ca2+ to leak into cytoplasm, stimulating muscle contraction.

Question 39

What is malignant hyperthermia?

Answer 39

Inherited mutation in RYR1. Rise in body temp in response to anesthetics

Question 40

What are the direct effects of hypothermia?

Answer 40

crystallization or intra and extracellular water→ high salt concentrations → cell injury

Question 41

What are the indirect effects of hypothermia?

Answer 41

Changes in circulation depending on the rate of chilling: 1. Slow chilling: vasodilation and increased vascular permeability→ edema and hypoxia (Ex: Trench Foot + gangrene) 2. Rapid chilling: vasodilation and increased blood viscosity → local ischemic injury and peripheral nerve degeneration. Gangrene can be seen. Vascular injury and edema seen as temp returns to normal.

Question 42

What happens in a low voltage (120 or 220v: home or workplace) electrical injury?

Answer 42

1. With low resistance (wet skin) can cause ventricular fibrillation. 2. Sustained current (caused by alternating current leading to tetanic muscle spasm→ prolonged grasp of wire) can cause burns (entry/exit sites and internal)

Question 43

What do high voltage (high-power lines or lightning) injuries cause?

Answer 43

Same mechanism as above but stronger. More likely to cause paralysis of medullary centers and extensive burns.

Question 44

What is at risk for damage from ionizing radiation?

Answer 44

Rapidly dividing cells and fetus

Question 45

So there is ionizing radiation. Is there non ionizing radiation?? If so, how are they different?

Answer 45

YEAH! Here's the difference: Nonionizing: UV, infrared light, microwave, sound→ can cause atoms in molecule to vibrate but can’t displace electrons Ionizing: X-ray, gamma rays, high-energy neutrons, alpha particles (2p+ 2n), beta particles (e-)→ can remove bound electrons. Electrons hitting other molecules releases more electrons→ known as ionization

Question 46

Where do we get exposed to ionizing radiation?

Answer 46

1. Medical imaging (CT, X-ray) 2. Cancer tx 3. Diagnostic and therapeutic radioisotopes

Question 47

What determines the biological effect of ionizing radiation?

Answer 47

1. Rate of delivery: breaks from radiation--> cell recovery 2. Field size: large dose to small field better than small dose to large field 3. Cell proliferation: ionization causes DNA damage. Rapid cell proliferation will increase # of cells damaged. ^damage--> bone marrow, gonads, GIT mucosa, lymphoid tissue 4. Oxygen effects/hypoxia: Radiolysis of H2O→ free radical production→ ROS formation → DNA damage. Tissue with poor oxygen supply (center of rapidly growing tumors) are less susceptible to effects of radiation. 5. Vascular damage: endothelial cells sensitive to radiation→ occlusion of vessels → impaired healing, fibrosis, chronic ischemic atrophy

Question 48

Sx of ionizing radiation?

Answer 48

Fibrosis, mutagenesis, carcinogenesis, teratogenesis.