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299 Cards in this Set
- Front
- Back
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What is the earliest known time that alcohol was used.
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6400 BC
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What was thought of alcohol in the middle ages?
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It was a remedy for all diseases, and whiskey was known as the water of life.
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What are the general types of chronic effects of alcohol?
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Medical and legal problems
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What is important to know about the therapeutic value of alcohol?
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It is nearly non-existent
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What is the basic process of producing alcoholic beverages?
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Fermentation
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What components are necessary to produce wine?
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Sugars, Water, and Yeast
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Why is distillation used?
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To obtain alcohol concentrations above those reached by fermentation
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What does "proof" mean?
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Proof is the strength of the alcoholic beverage and is denoted as twice the percent of alcohol in the beverage.
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How does the public view the effects of alcohol?
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They think it is stimulating
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Pharmacologically, how is alcohol considered?
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It is a depressant
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How does the misinterpretation of alcohol as a stimulant occur? (2 ways)
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In low concentrations, alcohol may enhance some excitatory neurons, and it also results from depression of the inhibitory control mechanisms in the brain.
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Which mental processes are first affected by alcohol?
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Memory and others dependent on training and previous experience, then concentration is lost
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What are the psychological effects of alcohol?
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Expansive personality, uncontrolled mood swings, and those associated with sensory and motor disturbances.
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When does anesthesia occur (mild, moderate, or severe intoxication)?
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It occurs during severe intoxication and is very close to the dose that causes respiratory depression.
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What does 100% BAL mean?
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There are 100g alcohol/100 mL of blood.
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What are the average BALs where effects start to occur of an abstainer, a moderate drinker, or a heavy drinker?
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abstainer = 0.05% BAL
moderate drinker = 0.07% BAL heavy drinker = 0.1% BAL |
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What generally occurs when a person reaches the BAL where effects start to occur?
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Lowered alertness, good feelings, psychic changes (personality), disruption of performance
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Why is there a disruption of performance in alcohol drinkers?
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Alcohol affects visual, motor, and visual motor skills
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Why do heavy drinkers develop effects at a higher BAL?
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Tolerance - not faster metabolism. Also, they have more practice and more desire concealing effects.
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At what BAL does the drinker have no comprehension of the world around them?
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0.30%
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At what BAL is the drinker most likely dead?
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0.60%
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At what BAL would 50% of the population be dead?
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0.40%
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At what BAL is the minimal fatal level?
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0.35%
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At what BAL does severe motor disturbance occur and sensory perception become greatly impaired?
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0.25%
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At what BAL is the drinker Dizzy and Disturbing?
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0.20%
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What is brain damage due to alcohol caused by?
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membrane fluidization, vitamin deficiency (niacin)
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What are symptoms of Wernicke's syndrome?
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confusion, ataxia and abnormal eye movement
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What are the cause and treatment for Wernicke's syndrome?
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Vitamin B1 deficiency
Treatment: improve nutrition |
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What is the main symptom of Korsakoff's Psychosis?
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patients are unable to remember recent events or learn new information
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What are the cause and treatment for Korsakoff's Psychosis?
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There is no known cause or treatment - it is irreversible
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Why do we often hear of Wernicke's syndrome and Korsakoff's Psychosis together?
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both disorders are seen in combination as Wernicke-Korsakoff syndrome
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What was believed about the mechanism of alcohol in the past?
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Alcohol was believed to dissolve in the lipids of membranes, which would lead to an increase in membrane fluidity and perturb the functions of proteins and channels
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What is now believed about the mechanism of alcohol?
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It has an effect on the excitatory (glutamate) and inhibitory (GABA) neurons. Alcohol inhibits glutamate, which leads to increased inhibitory effect by GABA.
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What effect does alcohol have on respiration?
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it depresses the ventilatory response to CO2, and moderate amounts can either stimulate or depress respiration. 0.40% BAL leads to respiratory depression
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What effect does alcohol have on sleep?
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it decreases latency to sleep and to REM sleep, increases deep, non-REM sleep, increases frequency and severity of sleep apnea, and increases the likelihood of waking up during latter hours of sleep
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What are some minor effects of alcohol on the cardiovascular system?
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increase in pulse (vasoconstriction of vital organs such as heart and brain), but vasodilation of skin blood vessels --> warm, flush skin
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What effect does chronic alcohol use have on the CVS?
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leads to cardiomyopathy
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What effects do moderate amounts of alcohol have on the body temperature?
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warmth and sweating --> heat loss
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What effects do larger doses of alcohol have on the body temperature?
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depression of CNS --> pronounced fall in body temperature (this is dangerous especially when the environmental temperature is low)
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What effect does moderate alcohol use have on Skeletal muscles?
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Large doses lead to CNS depression which leads to decrease in the amount of muscular work
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What effects does chronic alcohol use have on skeletal muscles, and can these effects be reversed?
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muscular damage, an increase in creatine phosphate in the blood plasma and yes, they may be reversible
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What nutritional effects does alcohol have?
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leads to vitamin deficiency --> this is secondary to GIT effects and liver disfunction
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What processes does alcohol affect in the GI tract?
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secretions: salivary, gastric, intestinal, and pancreatic
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What effect does alcohol have on the pancreas?
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it obstructs the pancreatic duct and leads to pancreatitis, or inflammation of the pancreas
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What effect does alcohol have on the GI tract in intoxicating doses?
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it leads to cessation of GIT secretory motor functions, delays absorption, and leads to vomiting, and pylorospasm in the stomach due to local irritation
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What effect does 10% alcohol have on the stomach?
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it stimulates gastric juice rich in HCl due to the psychological reflex stimulation exciting sensory endings in the buccal and gastric mucosa, and it increases the release of gastrin and histamine on the stomach?
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What effect does 20% alcohol have in the stomach?
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inhibits gastric secretion and peptic activity is decreased
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What effects do 40% alcohol have in the stomach?
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Very irritating to the mucosa, which leads to inflammation and erosive gastritis
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What effects does acute intoxication have on the liver?
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none, really
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What are the chronic effects of alcohol on the liver?
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Cirrhosis (fibrosis of the liver) associated with jaundice and accumulation of toxins in the body (7th leading cause of death in the US)
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What effect does nutrition have on whether or not someone gets cirrhosis from chronic alcohol use?
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Good nutrition does not prevent cirrhosis, but malnutrition intensifies the lesions
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Is cirrhosis irreversible?
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No - it is the 7th leading cause of death in the US
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How long does it take to get cirrhosis if the drinker drinks 1 pint of whiskey or more per day?
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10 years
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What is the mechanism of alcohol on the liver (also the metabolism of alcohol)?
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Ethanol is metabolized by MFO which forms acetaldehyde, and forms adducts with proteins, which inhibits enzymes. This also leads to lipid peroxidation of mitochondrial membranes and leads to glutathione depression.
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Is there a correlation between cancer and ethanol?
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Yes, there is a positive correlation between cancer and ethanol.
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What types of cancer are associated with ethanol?
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Mouth, tongue, pharynx, larynx, esophagus, stomach, pancreas, colon, rectum
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What is the name of the condition that results from a mother drinking alcohol while pregnant?
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Fetal Alcohol Syndrome
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What are some symptoms of fetal alcohol syndrome?
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CNS dysfunction, Low IQ, microcephaly (small head), slow growth, other malformations, abnormal neurobehaviorial development
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What are some characteristics of an infant's head with Fetal Alcohol Syndrome?
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Small circumference, small eyes, hypoplastic upper lip, short nose
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What is the mechanism of alcohol on a fetus?
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alcohol and acetaldehyde affect embryonic cellular proliferation and may injure the placenta
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What are the acute effects of alcohol on sex drive/characteristics?
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Leads to aggressive sexual behavior, and a decrease in sexual response in both males and females
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What are the chronic effects of alcohol in males (sexually)?
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impotence, sterility, and testicular atrophy -> leads to feminization
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Why does alcohol use result in feminization in males?
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Testicular atrophy --> decreased production of testosterone, also hepatic enzymes are working more to break down testosterone. these leads to hyperestrogenation
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What effect does alcohol have on the kidney?
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Diuretic effect due to inhibition of ADH secretion and a decrease in renal absorption
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What are the biogenic effects of alcohol?
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increases release of catecholamines which lead to increased catecholamine levels in the blood
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What does an increase in catecholamine levels in the blood cause?
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can cause transient hyperglycemia, pupillary dilation, and an increase in blood pressure
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What is there to know about absorption from ingestion of alcohol?
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there is rapid absorption in the stomach, and the max BAL is 30-90 minutes from the last drink
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What is there to know about absorption from inhalation of vaporized ethanol?
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Ethanol is well-absorbed through the lungs and may be fatal
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What are some factors affecting stomach absorption?
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Presence of food delays absorption of stomach and intestines (delays emptying time) Plain water decreases the concentration and carbonated liquids increase absorption
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What is there to know about distribution of alcohol?
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It does not distribute in fatty tissues and fat decreases the volume of distribution
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How is alcohol metabolized?
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Most of it is oxidized by alcohol dehydrogenase to acetaldehyde, which is converted to Acetyl CoA by aldehyde dehydrogenase, which is then oxidized through the citric acid cycle
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What is the rate of metabolism for alcohol?
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0.25-0.3 oz/ hour
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Where is alcohol metabolized?
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in the liver (98%) and the stomach
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What is an enzyme in addition to alcohol dehydrogenase that metabolizes alcohol and where does this occur?
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MFO (mixed function oxidase)in the endoplasmic reticulum of liver cells
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What type of kinetics does alcohol metabolism follow, and what does this mean for the sobering-up process?
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zero-order kinetics; it means sobering-up is a matter of waiting for the enzyme to do its job
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What is responsible for the toxic effects attributed to alcohol?
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Acetaldehyde
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How does the liver respond to chronic intake of alcohol? Does this only affect alcohol?
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It increases the level of microsomal MFO, which affects the metabolism of other drugs (no)
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What happens when a heavy drinker stops drinking?
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Alcohol disappears from the body and high enzyme activity continues for 4-8 weeks (leads to interactions with other drugs)
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Approximately how much alcohol is excreted in ts unoxidized form and by what organs?
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2-10% by the lungs and kidneys
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How is the concentration of alcohol in the blood related to the concentration of alcohol expired?
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Alcohol in blood is 2100 times the concentration of that in the expired air.
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What is a non-intrusive way of measuring BAL?
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Breathylizers assess concentration in the expired air and to find BAL, multiply by 2100.
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What are the standard alcohol beverages and how much does each contain?
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12oz can or bottle of beer
1 oz of 100-proof spirit 4 oz glass of wine Each contains 0.5oz of alcohol |
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What percentage of alcohol does the average beer contain?
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4.2%
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What percentage of alcohol does 100-proof spirit contain?
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50%
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What percentage of alcohol does a glass of wine contain?
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12%
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What should be considered when determining BAC based on amount of alcohol that is consumed?
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Alcohol is metabolized at a rate of 0.25-0.30 oz/hour
If we assume rate is 0.25 oz/hour, only half of the standard drink is metabolized |
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What rate should you drink to maintain a stable BAC?
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1 drink every 2 hours
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Who is more sensitive to alcohol: men or women?
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Women
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Why are women more sensitive to the effects of men?
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GIT absorption rate is higher in women, women have more fat than men (smaller volume of distribution), and men have more active ADM than women (they metabolize it faster)
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If both a man and a woman have 6 beers over 4 hours, who will be able to drive home?
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Neither, though the man will have a lower BAC
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What effect does alcohol have on phenytoin?
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it reduces the clearance of phenytoin
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What effect does alcohol have on Tolbutamide and other hypoglycemics?
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it reduces the half life
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What effect does alcohol have on acetaminophen?
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it increases the hepatotoxicity by increasing reactive intermediates and enhances glutathion depletion
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Why would taking alcohol with sedatives, hypnotics, anticonvulsants, or antidepressants be bad?
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They all depress the CNS, which would lead to extra depression of the CNS, which ultimately leads to death (respiratory failure)
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What are some drugs that alcohol interacts with to produce unpleasant effects simiilar to disulfarin effects?
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metronidazole, oral hypoglycemics, and cephalosporins
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What is alcohol contraindicative for?
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Hepatic diseases, GIT ulcers, cardiomyopathy, and pregnant women
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What BAL is considered definitely not under the influence?
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less than or equal to 0.05%
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What BAL is considered with other factors for guilt or innocence?
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0.05-0.1%
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What BAL is 1%considered driving under the influence?
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greater than or equal to 0.1%
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How much more likely is someone with a BAL of 0.1% to be involved in a fatal accident than someone with no ethanol in their blood?
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7 times
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How much more likely is someone with a BAL of 0.15% to be involved in a fatal accident than someone with no ethanol in their blood?
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25 times
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What is another name for alcohol withdrawal?
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Delirium Tremens
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When is physical dependence of alcohol revealed?
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When alcohol intake is stopped
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How long after cessation of alcohol do the stages of withdrawal take to begin?
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Stages are developed over a period of days
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What are some symptoms that accompany the stages of alcohol withdrawal?
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sensation of snakes or bugs crawling on the skin
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How many stages of withdrawal are there?
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4
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What are symptoms called when they stay for a long time (alcohol withdrawal)?
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"Protracted" symptoms
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What are some symptoms associated with stage 1 of alcohol withdrawal?
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tremor, excessive rapid heart beat, heavy sweating, loss of appetite, insomnia, nausea and vomiting
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What are some symptoms associated with stage 2 of alcohol withdrawal?
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hallucination, auditory, visual, and tactile signs
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What are some symptoms associated with stage 3 of alcohol withdrawal?
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delusions, disorientations, delirium, followed by amnesia
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What is a symptom associated with stage 4 of alcohol withdrawal?
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seizures
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What can be done to prevent stages 3 and 4 of alcohol withdrawal?
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medical treatment - diazepam in stage 1 or 2 will prevent stages 3 and 4
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How is a comatose patient with acute alcohol intoxication treated?
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stomach lavage, hemodialysis
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How is a patient not comatose with acute alcohol intoxication treated?
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wait for metabolization, if violent, give sedatives or antipsychotics (with great precaution)
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What symptoms does acetaldehyde produce?
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flushed face, vasodilation spreads in body, throbbing feeling in neck and head, pulsing headache, respiratory difficulty, vomiting, sweating, chest pain, hypotension, vertigo, and blurred vision
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Why are symptoms of acetaldehyde discussed when studying effects of alcohol?
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Acetaldehyde is an alcohol metabolite
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What are two drugs that can be given in response to chronic alcoholism?
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Disulfiram and naltrexane
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Is disulfiram a cure for chronic alcoholism?
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no, but it is a crutch for those who sincerely want to stop
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What does disulfiram lead to?
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Accumulation of acetaldehyde --> makes alcoholics feel like crap when they drink
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How was disulfiram discovered?
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It was used in the rubber industry and the workers developed a hypersensitivity to alcohol
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What type of drug is Naltrexane?
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Opioid agonist
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What effects of Naltrexane help chronic alcoholism?
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it reduces the euphorgenic effects (reduces the reinforcing effects) of alcohol
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What are some behavioral effects associated with a BAL of 0.05%?
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Lowered alertness, usually good feeling, release of inhibitions, and impaired judgment
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What are some behavioral effects associated with a BAL of 0.10%?
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Slowed reaction times and impaired motor function, less caution
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What are some behavioral effects associated with a BAL of 0.15%?
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Large, consistent increases in reaction time
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What are some behavioral effects associated with a BAL of 0.20%?
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Makred depression in sensory and motor capability, decidedly intoxicated
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What are some behavioral effects associated with a BAL of 0.25%?
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Severe motor disturbance, staggering, sensory perceptions greatly impaired; smashed!
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What are some behavioral effects associated with a BAL of 0.30%?
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Stuporous but conscious - no comprehension of the world around them
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What are some behavioral effects associated with a BAL of 0.35%?
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Surgical anesthesia: about LD 1, minimal level causing death
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What are some behavioral effects associated with a BAL of 0.40%?
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About LD 50
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What are some pathological hallmarks of Alzheimer's disease?
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Amyloid plaques and neurofibrillary tangles
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Where are common mutations that cause Alzheimer's disease?
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Amyloid precursor protein (APP), presenilins, apolipoprotein E4 allele, and Tau Proteins
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How many amino acids does APP contain?
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695, 751, or 770 amino acids
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Whhere is the gene is APP found?
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Chromosome 21
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What are three enzymes that cleave APP?
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a-secretase, b-scretase, g-secretase
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What is the function of a-secretase?
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It is neuroprotective
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What is the funciton of b-secretase?
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promotes b-amyloid formation
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How does b-secretase promote b-amyloid formation?
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It cleaves between Met 671 and Asp 672 with the help of BACE (b-site APP cleaving enzyme
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What is the function of g-secretase?
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it promotes b-amyloid formation
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How does g-secretase promote b-amyloid formation?
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It cleaves between Ile712, Thr714, or Val715, and may be presenilin 1
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Mutations near _-secretase and _-secretase result in Alzheimer's disease.
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b;g
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What is a rare result of a mutation in APP?
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increased b-amyloid levels
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What do mutations in presenilins increase the risk of?
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early onset AD and autosomal dominant AD
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What chromosome is Presenilin 1 located on?
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14
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What chromosome is Presenilin 2 located on?
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1
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What is the age of onset for individuals with a mutation in Presenilin 1?
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25-60 years
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What is the age of onset for the individuals with a mutation in Presenilin 2?
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45-84 years
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What ethnicity is most affected by mutations in Presenilin 2?
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Volga German families
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What effect do presenilin mutations have on the production of b-amyloid?
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they increase production, particularly the 42-43 amino acid forms
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What chromosome is the Apolipoprotein E4 allele found on?
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19
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What are the common alleles of ApoE?
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e2,e3 and e4
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In Caucasions, what is the most common allele of ApoE?
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ApoE3
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What is the second most common allele of ApoE?
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ApoE4
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What risk is associated with ApoE4?
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late onset AD
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Wat are the characteristics of Apolipoprotein E?
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it is a lipid transport molecule and component of very low density lipoproteins
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What is ApoE4 associated with?
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elevated plasma cholesterol
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For each ApoE4 allele that is inherited, how much earlier can we expect someone to develop AD?
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6-8 years
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How does ApoE4 bind to the LDL receptor?
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normally
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How does ApoE2 bind to the LDL receptor?
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poorly
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What is ApoE2 associated with?
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type III hyperlipoproteinemia
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For each ApoE2 allele that is inherited, how much later can we expect someone to develop AD?
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6-8 years
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What is the average age of onset for those with 4 homozygotes ApoE4 alleles?
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less than 70 years
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What is the average age of onset for those individuals with ApoE2 or ApoE3?
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Greater than 90 years
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Where are hyperphosphorylated Tau proteins found?
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in the helical filaments, which make up neurofibrillary tangles
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What type of proteins are Tau proteins?
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microtubule-associated proteins
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What do tau proteins do?
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they stabilize microtubules and interact with the actin cytoskeleton.
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What does phosphorylation of tau disrupt?
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tau association with microtubules
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Where are the mutations in tau proteins found?
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in fronto-temporal dementia with Parkinsonism
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What chromosome are mutations in tau proteins linked with?
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17
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How may the formation of paired helical filaments be linked to neuronal degeneration?
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tau proteins may be substrates for cleaved caspse-3, which is associated with apoptosis
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How can animal models help us to diagnose and treat alzheimer's?
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We see the same effects in mice with the mutations as in humans. We can study mice with these mutations to develop treatments.
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What neurotransmitter plays a major role in memory and attention?
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Acetylcholine
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What is the effect of acetylcholinesterase inhibitors?
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increase in acetylcholine because the enzyme that gets rid of it is inhibited
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What is some of the neurochemistry behind Alzheimer's disease?
|
Loss of choline acetyletransferase in the cerebral cortex and hippocampus, basal forebrain neurons that produce acetylcholine are degenerate
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What does the loss of cholinergic function lead to?
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loss of cognitive and memory functions
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What is the cholinergic hypothesis?
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replace acetylcholine to slow the decline of memory and cognitive function (by administering acetylcholinesterase inhibitors or muscarinic agonists)
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What are five common drugs for treatment of Alzheimer's?
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Tacrine(cognex), Donepezil(aricept), Rivastigmine(exelon), Galantamine (reminyl), Memantine (namenda)
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Which of the five drugs for Alzheimer's are acetylcholinesterase inhibitors?
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Tacrine(cognex), Donepezil(aricept), Rivastigmine(exelon), Galantamine (reminyl)
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What are some common adverse effects among acetylcholinesterase inhibitors?
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nausea, vomiting, diarrhea, anorexia, fatigue, abdominal pain, dyspepsia
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Which of the acetylcholinesterase inhibitors peaks the quickest?
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Rivastigmine(exelon), and Galantamine(reminyl)
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Which of the acetylcholinesterase inhibitors has the highest absorption?
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Donepezil(aricept)
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What are some characteristics of Tacrine(cognex)?
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Acetylcholinesterase inhibitor, peaks 1-2hrs, absorption 5-30%, hepatic toxicity, low selectivity for CNS acetylcholinesterase
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What are some characteristics of Donepezil(aricept)?
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Acetylcholinesterase inhibitor, peaks 3-4hrs, absorption near 100%, once a day drug
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What are some characteristics of Rivastigmine (exelon)?
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Acetylcholinesterase inhibitor, derived form physostigmine, peaks at 1hr, absorption 36%, minimal hepatic metabolism
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What are some characteristics of Galantamine(reminyl)?
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Acetylcholinesterase inhibitor, isolated from daffodil bulb, peaks 1 hr, absorption 90%, metabolized by cyp2d6 and 3a4
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What are the key characteristics of Memantine(namenda)?
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NMDA glutamate receptor antagonist (prevents glutamate-mediated neuronal toxicity), useful in later stages, peaks 4-6hrs, absorption 100%
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What are some adverse effects of Memantine(namenda)?
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agitation, urinary incontinence, and infections, insomnia, and diarrhea
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What are some other therapies for Alzheimer's (besides the main 5 drugs)?
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prevent inflammation, prevent amyloid plaque formation, Amyloid therapies, muscarinic agonists, antioxidants, estrogen replacement therapy
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How do we prevent inflammation?
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NSAIDS, peroxisome proliferator-activated receptor-g agonists (PPAR-g), block glial proliferation
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What drug is being developed to prevent amyloid plaque formation?
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Alzhemed - is in phase 2 clinical trials
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What are some amyloid therapies?
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inhibitors of b- and g-secretases, inhibitors of amyloid plaque formations (uncaria tomentosa), vaccine for b-amyloid
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What was a muscarinic agonist that could have helped with alzheimer's, but was discontinued?
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Xanomeline
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What are some characteristics of xanomeline?
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selective m1/m4 agonist
improved cognitive function and alleviated psychosis in alzheimer's patients, subject to first pass effect, has high side effect occurance (development was discontinued) |
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What are some muscarinic agonists that are being developed currently?
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AF267B, and CDD-0102
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What are some antioxidants used to prevent alzheimer's?
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vitamin e, vitamin c, and resveritrol (a component of red wine
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What effect do antioxidants have on alzheimer's disease?
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there is little evidence of therapeutic benefit after diagnosis, but they decrease the risk of developing alzheimer's
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What are some actions of adrenergic ligands?
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excitatory action on smooth muscle contraction and glandular secretion, inhibitory action on smooth muscle contraction, cardiac excitation, metabolic activity, endocrine modulation, CNS-respiratory stimulation, wakefulness, psychomotor activity, appetite suppression, presynaptic regulation of neuronal release (usually inhibitory)
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Where are adrenergic ligands direct acting?
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at a- and b- adrenergic receptors (norepinephrine, phenylephrine, and terbutaline)
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What are adrenergic ligands that are indirect acting?
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Amphetamine - increases release of norepinephrine; cocaine, desipramine - block transport of norepinephrine; pargyline, entacapone - block metabolism of norepinephrine
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What is an example of an adrenergic ligand that has a mixed (direct and indirect) way of acting?
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Ephedrine enhances catecholamine release and activates a and b receptors.
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What are some structure activity relationships with b-phenylethylamine?
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substitution on a carbon, substitution on b carbon, substitution on phenyl ring, n-alkylation
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What effect does substitution on the a carbon of b-phenylethylamine have?
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it blocks metabolism by MAO
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What effect does substitution on the b carbon of b-phenylethylamine have?
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it increases agonist activity, but decreases CNS penetration
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What effect does substitution on the phenyl ring of b-phenylethylamine have?
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hydroxylation is important for agonist activity and potency, meta and para hydroxylation (epinephrine and norepinephrine), and decreases CNS penetration
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What effect does N-alkylation of b-phenylethylamine have?
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leads to increase in b-receptor activity (as in isoproterenol). addition of methyl (epinephrine), and addition of isopropyl (isoproterenol)
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What does the action of sympathomimetic drugs depend on?
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the selectivity for a- vs b-adrenergic receptors & location is important
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What are some exaples of the activity of sympathomimetic drugs?
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norepinephrine activates a-receptors better than b-receptors, epinephrine activates b-receptors better than a-receptors
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What are some results of false transmittors?
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some indirect acting amines can replase norepinephrine in synaptic vesicles, may be responsible for adverse effects of MAO inhibitors
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How can indirect amines replace norepinephrine?
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hydroxylation derivatives are maintained due to hydrophilic nature, and can result in depletion of norepinephrine
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How can false transmittors be responsible for the adverse effects of MAO inhibitors?
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Tyramine formed is deaminated and cleared, but a blockaed of MAO results in transport to the sympathetic nerve terminals. b-hydroxylation results in oxtopamine, which is stored in synaptic vesicles. Elevated levels of tyramine can produce hypertensive crisis in patients taking MAO inhibitors because it promotes a massive release of norepinephrine
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What types of receptors does epinephrine affect?
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a- and b- adrenergic receptors
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What are some effects of epinephrine on blood pressure?
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It is a vasopressor-increases blood pressure following iv infusion, increases strength of cardiac contractions and heart rate, and promotes vasoconstriction in vascular beds
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What are some vascular effects of epinephrine?
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it depends on site of action - decreases cutaneous blood flow by constricting precapillary vessels, increases blood flow to skeletal muscles, little impact on cerebral blood flow, increases renal vascular resistance and reduces renal blood flow
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How does epinephrine increase blood flow to skeletal muscle?
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b2 vasodilation predominates over a-receptor vasoconstriction
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How does epinephrine increase renal vascular resistance and reduce renal blood flow?
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it decreases the secretion of Na, K, and Cl
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What are some cardiac effects of epinephrine?
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it is a powerful cardiac stimulant and is a potent activator of b1 adrenergic receptors --> increases in heart rate, force of contraction, and cardiac output (efficiency is reduced)
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What are some effects of epinephrine on smooth muscle?
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it depends on the prevalance of different adrenergic receptors
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What effects does epinephrine have on the GI smooth muscle?
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it relaxes GI smooth muscle due to activation of both b and a receptors
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What effects does epinephrine have on uterine contractions?
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it generally increases them, but during the last month it inhibits uterine tone and contractions (b2 agonists are used to delay premature labor)
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What effect does epinephrine have on the bladder?
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hesitancy in urination
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What respiration effects does epinephrine have?
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It leads to relaxation of bronchial smooth muscle
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What are the CNS effects of epinephrine?
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It is polar, so it has limited access to the brain, but it causes restlessness, apprehencion, headache, and tremor (somatic manifestations of anxiety)
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What are some effects of epinephrine on human metabolism?
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elevates glucose and lactate, modulates insulin secretion, increases glycogenolysis, and stimulates release of fatty acids by activating triglyceride lipase
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How does epinephrine monitor insulin secretion?
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decrease is mediated by a2 receptors (predominates) and an increase is mediated by b2 receptors
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What receptors does epinephrine bind to to increase glycogenolysis?
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b2 receptors
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What doe the activation of triglyceride lipase by epinephrine lead to?
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increased metabolism
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What is there to know about the absorption of epinephrine?
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There is limited absorption following oral and subcutaneous administration, and rapid absorption after injection, iv, or inhalation
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What is there to know about metabolism of epinephrine?
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there is rapid inactivation by COMT and MAO
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What is there to know about the toxicity of epinephrine?
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Side effects include reslessness, headache, tremor, palpitations, cardiac arrhythmia, and cerebral hemmorhage
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How can the side effects of epinephrine be treated
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rest, quiet, and reassurance
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What are some therapeutic uses of epinephrine?
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may restore cardiac rhythm in patients with cardiac arrest, previously used to relieve respiratory distress due to bronchospasm, relieves hypersensitivity reactions to drugs, prolongs actions of local anesthetics, and leads to hemostasis
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How is norepinephrine different from epinephrine?
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it is effective differently in stimulating a and b receptors: less potent at a receptors, very weak as a b2 agonist, but is equipotent with epinephrine in stimulating b1 receptors
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What are some cardiovascular effects of norepinephrine?
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increases blood pressure, cardiac output is unchanged or decreased, peripheral vascular resistance increases in vascular eds, renal blood flow is reduced, and mesenteric vessels are restricted, and hepatic blood flow is reduced
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What is there to know about norepinephrine ADME?
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It is ineffective orally, poorly absorbed following subcutaneous injection, there is rapid metabolism via MAO and COMT, and it is excreted in the urine
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How is norepinephrine toxic?
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elevated blood pressure, hypertension at high doses, necrosis and sloughing at site of iv injection, reduced blood flow to kidney
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How can the impaired circulation at the injection site of norepinephrine be relieved?
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use of phentolamie (a receptor antagonist)
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What are some therapeutic uses of norepinephrine?
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used in treatment of shock, treatment of low blood pressure
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What diseases is dopamine associated with?
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Parkinson's disease and schizophrenia
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What effects does dopamine have on the peripheral tissues?
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exerts diuretic natriuretic effects
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Where is dopamine synthesized?
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in the proximal tubule
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What are some cardiovascular effects of dopamine?
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vasodilation in renal, mesenteric and coronary vascular beds, decreases Na transport in the renal tubule, has a positive inotropic effect on myocardium, increases norepinephrine release and increases blood pressure
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What receptors does dopamine act on in the renal, mesenteric, and coronary beds to cause vasodilation?
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D1 receptors
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Why does dopamine result in vasodilation?
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formation of cAMP
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what receptors does dopamine act on in the renal tubule to decrease Na transport?
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D1 receptors
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What receptors does dopamine act upon to cause a positive ionotropic effect in the myocardium?
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b1 receptors
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What are some precautions of dopamine?
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correct hypovolemia, and there is a potential for excessive sympathomimetic activation
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What are some adverse effects of dopamine?
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nausea, vomiting, tachycardia, anginal pain, arrhythmias, headache, and hypertension
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Where is dopamine contraindicated?
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in patients taking MAO inhibitors
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What are some therapeutic uses of dopamine?
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treatment of severe congestive failure, treatment of cardiogenic and septic shock, intensive care, and vasodilator effects
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For what condition are b2 agonists useful?
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in the treatment of asthma
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What is the mechanism of action for b2 agonists in asthma?
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they decrease adverse effects associated with cardiac b2 receptor activation
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How are adverse effects limited in the treatment of asthma?
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Inhalaton takes the drug directly to the active site.
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What are some adverse effects related to excessive activation of b2 receptors?
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tremor, tachycardia, arrhythmias or myocardial ischemia in those with cardiac disease, interaction with MAO inhibitors, connection between long-term use and death or near death from asthma(due to tolerance)
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What type of receptors do the drug isoproterenol activate?
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b receptors
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Is isoproterenol selective?
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no, it is a non-selective b agonist
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What effect does isoproterenol have on the CV system?
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it decreases vascular resistence, increases cardiac output, and decreases diastolic blood pressure
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What is there to know about the ADMET properties of isoproterenol?
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Absorbed parentarally or as an aerosol, metabolized by COMT, but is a poor substrate for MAO, and has adverse effects such as palpatations, tachycardia, headache
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What are some therapeutic uses of isoproterenol?
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stimulate heart rate in patients wth bradycardia or heart block
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What are some examples of b2 agonists?
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metaproterenol, terbutaline, albuterol, isoetharine, pirbuterol, bitolterol, fenoterol, formoterol, procaterol, salmeterol, ritodrine
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What are drugs with improved b2 selectivity and improved oral bioavailability?
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metaproterenol, tertbutaline
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What are some examples of a1 agonists?
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phenylephrine, mephenteramine, metaraminol, midodrine
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What happens when a1 receptors in the CV system are activated?
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decreases in vascular resistence, elevate blood pressure, usefull in treatment of hypotension or shock, nasal decongestants
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What is a good example of an a2 agonist?
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Clonidine
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What is clonidine used for?
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The treatment of hypertension; it decreases the outflow of sympathetic nervous system activity from the brain
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What is there to know about the ADMET of clonidine?
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well absorbed orally, half life of 6-24 hours, eliminated via the kidney, adverse effects include dry mouth and sedation
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What are the results of nicotinc antagonists?
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muscle paralysis
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What type of ligand is a nicotinic antagonist?
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cholinergic ligand
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What type of ligand are nicotinic agonists?
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cholinergic ligand
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What are some nicotinic agonists?
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Analogs of nicotine, analogs of epibatidine, and other compounds
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What are some analogs of nicotine that are nicotinic agonists?
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ABT-41B, isoxazole replaces pyridine ring of nicotine (useful in alzheimer's)
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What are some analogs of epibatidine that are nicotinic agonists?
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Epibatidine, Epiboxidine
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What are some compounds that are nicotinic agonists that don't fit into the catagories of analogs of nicotine or epibatidine?
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ABT-594(analgesic properties), and Altnicline (Parkinson's)
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What muscles are paralyzed by competitive nicotinic antagonists?
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small muscles relax before limb and trunk muscles, intercostal and diaphragm muscles also become paralyzed (respiration ceases)
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What is an example of a depolarizing nicotinic antagonist?
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Succinylcholine
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What do depolarizing nicotinic antagonists produce?
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muscle fasciculations followed by muscle relaxation
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What occurs with treatment by depolarizing nicotinic antagonists?
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transient apnea, and muscle soreness from succinylcholine
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How can paralysis by depolarizing nicotinic antagonists be maintained?
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Through continuous infusion
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What are some ways to classify nicotinic antagonists?
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Duration of action, chemical nature, where they act best
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What are some examples of nicotinic antagonists with a long duration of action?
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d-tubocurarine, metocurine, pancuronium
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What are some examples of nicotinic antagonists with an intermediate duration of action?
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vecuronium and atracurium
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What are some nicotinic antagonists with a short duration of action?
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mivacurium
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What are some classifications of niotinic antagonists based on chemical nature?
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Quaternary derivitives, alkaloids, ammonio steroids, and benzylisoquinolines
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What are some examples of alkaloids?
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d-tubocurarine, alcuronium
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What are some examples of ammonio steroids?
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pancuronium, pipecuronium, rocuronium
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What are some examples of benzylisioquinolines?
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doxacurium, mivacurium
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What are some classifications of nicotinic antagonists based on where they act best?
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Neuromuscular juction nicotinic receptor antagonists, autonomic ganglia nicotinic receptor antagonists
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What do neuromuscular junction nicotinic receptors mediate?
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contraction of skeletal muscle
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What are some clinical uses of neuromuscular blocking agents?
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Adjuvant in surgical anesthesia, valuable in orthopedic procedure, facilitate intubation, administered parentally
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How are neuromuscular blocking agents adjuvant in surgical anesthesia?
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they help obtain relaxation of skeletal muscle to facilitate surgical procedures, which means lighter anesthesia can be used, risk of respiratory and cardiovascular depression, and shortens postoperative recovery
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How are neuromuscular blocking agents valuable in othopedic procuedures?
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They help with correction of dislocated limbs, and alignment of fractures
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What are some examples of Neuromuscular junction nicotinic receptor antagonists?
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Snake venoms, curare (and derivatives), decamethonium, gallamine, and succinylcholine
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what is curare?
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various arrow poisons from south america
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What is curare used for?
|
immobilizing and paralyzing game
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What are som derivatives of curare?
|
tubocurarine, metocurine and alcuronium
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What is mediated by autonomic ganglia nicotinic receptor antagonists?
|
synaptic transmission at the ganglion
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What are some therapeutic uses of autonomic ganglia blockers?
|
Used to treat hypertension and effects depend on the predominance of sympathetic or parasympathetic tone at effector sites
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What occurs if the sympathetic tone is predominant at the effector sites?
|
Ganglionic blockade results in vasodilation, increased blood flow, and hypotension of arterioles, and results in dilation, peripheral pooling of blood and decreased cardiac output in veins
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What occurs if the parasympathetic tone is predominant at the effector sites?
|
Ganglionic blockade results in tachycardia in the heart, and it results in mydriasis in the iris
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What are some examples of autonomic ganglia nicotinic receptor antagonists?
|
trimethaphan, mecamylamine(only blocker currently used), snake venoms eg a-bungarotoxin (don't bind well) Hexamethonium
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