Path Chapter 9: Environmental and Nutritional Diseases (pages 414-420)
Hormone replacement therapy (HRT):
- The most common type of HRT is giving them estrogen and progesterone together
o Because of risk of uterine cancer, estrogen therapy alone is only used for women who have had a hysterectomy
- HRT used to be used in postmenopausal women to prevent osteoporosis and MI
o A study was done then, that found HRT did prevent fractures, but it ↑ the risk of breast cancer and thromboemobolism, and had no effect on preventing cardiovascular disease
- HRT increases the risk of breast cancer after taking it for 5-8 years
- HRT protects from atherosclerosis and heart disease in women under 60, but those who started taking it after 60 get no effect
- HRT increases the risk for venous thromboembolism
Oral contraceptives – inhibit ovulation and prevent implantation
- Most OCs have synthetic estradiol and progestin, but some only have progestin
- OCs can cause:
o Thromboembolism – OCs increase the risk of venous thrombosis and pulmonary embolism, especially if they have a Leiden (factor 5) or prothrombin mutation
§ The risk is due to it triggering an acute phase response that raises C reactive protein, and decreases #’s of anticoagulants
o Cardiovascular disease – OCs increase the risk of MI in women who smoke, and women who don’t who are older than 35
o Hepatic adenoma – benign hepatocyte tumor
- OCs decrease the risk for endometrial and ovarian cancers
Anabolic steroids – synthetic versions of testosterone, often used at doses way higher than therapeutic use would use
- The high test levels inhibits making and release of LH and FSH, and increases the amount of estrogens, cause the steroids get made into estrogens
- Anabolic steroids stunt growth in adolescents, cause acne, gynecomastia, and testicular atrophy in males, and cause facial hair growth and menstrual changes in women
- Test also can cause psychiatric problems, MI, and hepatic cholestasis (bile backing up into liver)
Acetaminophen is the most commonly used analgesic in the US, so acetaminophen toxicity is common
- Acetaminophen toxicity causes half of cases of acute liver failure, with 1/3 leading to death
- Most overdoses of acetaminophen in the US are not intentional
- Under therapeutic doses, about 95% of acetaminophen is detoxed in the liver by phase 2 enzymes, and then gets excreted in the urine as glucuronate or sulfate conjugates – page 417
- The other 5% is metabolized by CYPs, mainly CYP2E, into N-acetyl-p-benzoquinoneimine (NAPQI)
- NAPQI is usually conjugated with glutathione (GSH), but large doses causes unconjugated NAPQI to accumulate and cause hepatocellular injury, leading to centrilobular necrosis and liver failure
o NAPQI covalently binds liver proteins, causing damage to cell membranes and mitochondria
o NAPQI also decreases glutathione, making hepatocytes more susceptible to reactive oxygen species-caused injury
o So more acetaminophen = more NAPQI = more glutathione used up = oxidative stress
- Alcohol induces CYP2E in the liver, so acetaminophen is more toxic at lower doses in chronic alcoholics
- Acetaminophen is really safe though. The window from therapeutic (0.5g) to toxic (15-20g) is big
- Symptoms of acetaminophen toxicity start with nausea, vomiting, diarrhea, and sometimes shock, then jaundice shows up a few days later
- Overdoses of acetaminophen can be treated if it’s been within 12 hours, by N-acetylcysteine, which restores glutathione
- Serious overdoses cause liver failure, starting with centrilobular necrosis, that then extends to whole lobules, so they need a liver transplant to survive
Aspirin (acetylsalicylic acid)
- One unintentional way to overdose on salicylic acid is excessive use of ointments with wintergreen oil in them – has methyl salicylic acid
- Acute salicylate OD causes alkalosis, due to the respiratory center in the medulla being stimulated
- Next, you get metabolic acidosis and accumulation of pyruvate and lactate, from uncoupling of oxidative phosphorylation and inhibition of the Krebs cycle
- Metabolic acidosis enhances formation of nonionized salicylates, which then diffuse into the brain and cause things like nausea and coma
- Chronic aspirin toxicity (salicylism) happens in people who take large doses daily for chronic pain or inflammatory conditions
o Symptoms of chronic salicylism are headaches, dizziness, tinnitus (ringing ears), problems hearing, confusion, drowsiness, nausea, vomiting, and diarrhea
o This can then progress to convulsions and coma
o Also, chronic salicylism can cause acute erosive gastritis, which can lead to GI bleed and stomach ulcers
§ Bleeding is made worse by aspirin inhibiting clotting
o Petechial hemorrhages can show up in the skin and organs
- Years of mixing aspirin and acetaminophen can cause tubulointerstitial nephritis with renal papillary necrosis, called analgesic nephropathy
Cocaine – sold as cocaine hydrochloride diluted with some look-alike, like talcum powder
- Cocaine can be snorted, or dissolved in water and injected
- When you crystalize cocaine, you get crack – called that cause of the “cracking” sound it makes as you heat it
o Both crack and cocaine do the same thing, but crack is more potent
- Cocaine produces an intense euphoria & stimulation, making it one of the most addicting drugs
- There is usually no physical dependence on cocaine, but psychologic withdrawal is profound and hard to treat
- Acute overdose of cocaine can cause seizures, arrhythmias, and respiratory arrest
- Cocaine effects:
o Cardiovascular – cocaine acts like the symp system. It facilitates neurotransmission in the CNS, where it blocks reuptake of dopamine, and the adrenergic nerve endings, where it blocks reuptake of epinephrine and norepinephrine
§ This causes dopamine and epi/norepi to accumulate in synapses, causing excess stimulation
§ This causes tachycardia, hypertension, and peripheral vasoconstriction
§ Cocaine can also cause an MI, by causing coronary artery vasoconstriction, and enhancing clot formation
· It cause ischemia by increased heart muscle demand for oxygen by acting like symps, and at the same time decreases coronary blood flow
§ Cigarette smoking makes the cocaine-caused heart vasoconstriction worse
§ These cardiovascular effects of cocaine are not dose-related, and can happen any time you take it
o CNS – cocaine causes hyperpyrexia (extreme fever) and seizures
o Pregnancy – cocaine can decrease blood flow to the placenta, causing fetal hypoxia and possible abortion. Also neuro development can be impaired in chronic cocaine users
o Chronic cocaine use can perforate the nasal septum in snorters, decrease lung diffusing capacity in inhalers, and cause dilated cardiomyopathy
Heroin – addictive opiod derived from the poppy plant, and closely related to morphine
- Heroin is even more harmful than cocaine, and usually taken IV
- Effects of heroin are euphoria, hallucinations, somnolence (state of near sleep, wanting to sleep, or sleeping for a really long time, think what happened to stephanie), and sedation
- Consequences of heroin:
o Sudden death – by respiratory depression, arrhythmia and cardiac arrest, and severe pulmonary edema
o Pulmonary injury – like edema, septic embolism from lung abscess, easy to get infected, and foreign body granulomas (of talc or quinine, which are added to the heroin)
o Infection – this is common. The 4 most common sites of infection are the skin, heart valves, liver, and lungs
§ 1/10 of heroin users have endocarditis in the right tricuspid heart valve, most often by staph aureus
§ Viral hepatitis is the most common infection for addicted heroin users, from sharing contaminated needles
· More AIDS in heroin users for the same reason
o Skin lesions – the most common hallmark of a heroin user, includes abscesses, cellulitis, and ulcerations from needle use
§ Scarring at injection sites, hyperpigmentation over commonly used veins, and thrombosed veins are commonly seen
o Kidney problems – amyloidosis (secondary to skin infections) and glomerulosclerosis, which both cause heavy proteinuria and nephrotic syndrome
Amphetamines:
- Methamphetamine (aka “speed” or “meth”) – stronger effects in the CNS than amphetamine
o Works by releasing dopamine int eh brain, which inhibits presynaptic neurotransmission at corticostriatal synapses, slowing down glutamate release
o Meth produces a feeling of euphoria, followed by a “crash”
o Long-term use leads to violent behaviors, confusion, paranoia, and hallucinations
- 3,4 methylenedioxymehamphetamine (MDM, aka “ecstasy”)
o Taken orally
o Causes euphoria and hallucinations for 4-6 hours, due to serotonin release in the CNS
o Ecstasy also interferes with serotonin making, causing a decrease in serotonin that is only slowly replenished
Marijuana (aka “pot”) – made from cannabis leaves, which have the psychoactive substance tetrahydrocannabinol (THC)
- About 1/10 or less of THC is absorbed when it’s smoked in a hand-rolled cigarette (aka “joint”)
- Marijuana helps with nausea from chemotherapy, & decreases pain in some chronic conditions
- Marijuana distorts sensory perception, and impairs motor coordination, both acutely for only 4-5 hours
o Continued use causes problems with cognition, and an inability to judge time, speed, and distance
- Marijuana increases heart and sometimes blood pressure, and can cause angina in someone with heart disease
- In the lungs, marijuana can cause laryngitis, pharyngitis, bronchitis, cough and hoarseness, asthma, and airway obstruction
o Marijuana cigarettes have the same carcinogens as cigarettes, and increases the tar you inhale
- We have an endogenous cannabinoid system in our bodies, that consists of cannabinoid receptors CB1 and CB2, as well as lipid ligands called endocannabinoids
o This system regulates the hypothalamic-pituitary-adrenal axis, and regulates control of appetite, food intake, energy balance, and fertility and sexual behavior