Environmental Path 3 Flashcards
Let’s talk about the metabolism of alcohol
- Stomach/SI - Absorb ethanol without altering it
- 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) - Acetaldehyde made by metabolism, converted to acetate by acetaldehyde dehydrogenase, acetate used in mitochondrial respiratory chain
- 10% excreted unaltered in sweat, breath, urine
Let’s talk about how the sx of alcohol change depending on how much you have.
- 80 mg/dL (3 beers, 15 ounces wine, 4-5 ounces 80 proof liquor) = Drunk driving
- 200 mg/dL = Drowsiness
- 300 mg/dL = Stupor
- > 300 mg/dL = Respiratory arrest/coma eventually
- 700 mg/dL = Limit chronic alcoholics can tolerate due to 5-10x increase in CYP induction
What are the toxic metabolites in alcohol? Just list them now, more detail in next cards
- Acetaldehyde
- Decreased NAD
- ROS
- Endotoxin
Acetaldehyde. Tell more more.
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
Decreased NAD. DO TELL ME MORE PLEASE
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)
Where are all these ROS coming from?
Source: CYP2E1 of ethanol makes ROS = lipid peroxidation in hepatocyte membranes
What’s this endotoxin you speak of?
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
What are we saying the effects of acute alcoholism are?
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
What about that chronic alcoholism? More is better eh?
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
So no more alcohol for us ever again in the rest of our lives??? WAHHHHH
Nope, you just need to pick the right stuff:
250 mL of wine per day = Good
- Increased HDL
- Reduced platelet aggregation
- Lower fibrinogen levels
AW YEAH
Normal dosing for Acetaminophen
Normal dose = 0.5 g
Overdose = 15-25 g
Discuss the metabolism of acetaminophen?
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
So what’s this NAPQI you speak of? Why is it so bad?
Covalent bonding to hepatic proteins → damage to cell membranes and mitochondrial dysfunction
Depletion of glutathione (GSH) → Hepatocytes more prone to damage by ROS
What are the sx of acetaminophen overdose?
- N/V/D
- Shock
- Jaundice
- Liver failure
Tx of acetaminophen overdose?
Within 12 hours = N-Acetylcysteine = Restores GSH levels.
Liver centriolobular necrosis = Liver Transplant
Discuss the pathophys involved with aspirin toxicity?
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
What are the sx associated with aspirin toxicity? (defined as 3g+/day
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
What can happen with you’re doubling up on aspirin and acetaminophen
Taken chronically → Tubulointerstitial nephritis with renal papillary necrosis (analgesic nephropathy)
Cocaine. Talk about the composition and types of this drug.
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
Addiction with cocaine?
Psychological addiction, NOT physical. Withdrawal is profound.
CV sx associated with cociane?
- Sympathomimetic, blocks reuptake of Epi and NE and stimulates release of NE presynaptically → Tachycardia, HTN, peripheral vasoconstriction.
- Enhances platelet aggregation and thrombus formation → Coronary artery vasoconstriction → Myocardial ischemia.
- Enhanced sympathomimetic activity + ion transport disruption (Na+, K+, Ca2+) → Lethal arrhythmias
- Development of dilated cardiomyopathy (doesn’t say why)
CNS effects of cocaine?
Blocks reuptake of Dopamine → euphoria and hyperpyrexia (very high fever due to dopaminergic pathways of body temperature control) and seizures
What about cocaine during pregnancy?
Decreases in blood flow to placenta → Fetal hypoxia, degeneration of neural development and potentially spontaneous abortion
What lab will be + for a cocaine user
(+) BE (benzoylecgonine)
What’s the deal with heroin? Where does it come from?
Poppy plant, closely related to morphine.
Cut with Talc or quinine.
Administered intravenously or subQ
CNS effects of heroine?
Euphoria, hallucinations, somnolence, sedation
Can you get sudden death from heroin?
Yes,
- Profound respiratory depression
- Arrhythmia
- Cardiac arrest
- Severe pulmonary edema
What are the effects of cocaine in the lungs?
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
What kind infections are common with heroin use?
- Right sided tricuspid - S. Aureus
- Viral hepatitis: most common infection
- HIV due to needle sharing
What skin shit happens with heroin use?
Cutaneous lesions from subQ injections, hyperpigmentation over injection sites
Kidney stuff with heroin?
- Amyloidosis from skin infections
- Segmental glomerulosclerosis.
- Proteinuria
- Nephrotic syndrome
What lab will you see with heroin use?
6-MAM (monoacetylmorphine)
How do you treat a heroin overdose?
methadone therapy
What bad things do burns cause?
- Shock: Shift of body fluids into interstitial compartment 2. Pulmonary and generalized edema→ Vascular leakiness
- Hypermetabolic state→ heat loss and need from nutritional support.
- Infection→ most common organism=*Pseudomonas aeruginosa, MRSA, Candida.
- Airway and lung injury from inhalation → complete or partial airway obstruction
Classification of burns
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
What kind of injuries do we see in hyperthermia
- Heat cramps: from loss of electrolytes from sweating. A/w vigorous exercise
- Heat exhaustion: most common. From failure of cardiovascular system to compensate for hypovolemia caused by dehydration. Onset is sudden with prostration and collapse
- Heat stroke: A/w high temp, high humidity and exertion. At risk: older people, people undergoing physical stress, people with CV dz.
More on heat stroke. What is the pathophys involved here
- Body temp>40C→ multiorgan dysfunction.
- Generalized vasodilation→ peripheral blood pooling and ineffective circulation.
- Sustained contractions of skeletal muscle contractions→ muscle necrosis and rhabdo.
Why are there sustained muscle contractions seen in heat stroke?
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.
What is malignant hyperthermia?
Inherited mutation in RYR1. Rise in body temp in response to anesthetics
What are the direct effects of hypothermia?
crystallization or intra and extracellular water→ high salt concentrations → cell injury
What are the indirect effects of hypothermia?
Changes in circulation depending on the rate of chilling:
1. Slow chilling: vasodilation and increased vascular permeability→ edema and hypoxia (Ex: Trench Foot + gangrene)
- 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.
What happens in a low voltage (120 or 220v: home or workplace) electrical injury?
- With low resistance (wet skin) can cause ventricular fibrillation.
- Sustained current (caused by alternating current leading to tetanic muscle spasm→ prolonged grasp of wire) can cause burns (entry/exit sites and internal)
What do high voltage (high-power lines or lightning) injuries cause?
Same mechanism as above but stronger. More likely to cause paralysis of medullary centers and extensive burns.
What is at risk for damage from ionizing radiation?
Rapidly dividing cells and fetus
So there is ionizing radiation. Is there non ionizing radiation?? If so, how are they different?
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
Where do we get exposed to ionizing radiation?
- Medical imaging (CT, X-ray)
- Cancer tx
- Diagnostic and therapeutic radioisotopes
What determines the biological effect of ionizing radiation?
- Rate of delivery: breaks from radiation–> cell recovery
- Field size: large dose to small field better than small dose to large field
- Cell proliferation: ionization causes DNA damage. Rapid cell proliferation will increase # of cells damaged. ^damage–> bone marrow, gonads, GIT mucosa, lymphoid tissue
- 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.
- Vascular damage: endothelial cells sensitive to radiation→ occlusion of vessels → impaired healing, fibrosis, chronic ischemic atrophy
Sx of ionizing radiation?
Fibrosis, mutagenesis, carcinogenesis, teratogenesis.
