Nervous System- Alcohol By Schriefer

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Nervous System- Alcohol by Schriefer

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Nervous System- Alcohol by Schriefer

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Pharmacology of Alcohol

what's most susceptible?

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Central nervous system – most susceptible
Cellular mechanism of action – several hypotheses:
An action on the GABA receptor – increases GABA – mediated inhibition. This action may mediate sedative and ataxia effects.
May also inhibit NMDA receptors causing blackouts (NMDA AND MEMORY!)
An action on neural membrane (alter fluidity of the membrane) may mediate effects at high concentrations.

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General psychological effects of the CNS

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Central Nervous System
General psychological effects
Emotional behavior – euphoria, loquaciousness, aggression, sedation
Intermediate term memory loss and altered time sense
Disrupts sleep-type EEG (REM suppression)
Chronic changes
Not very potent so relatively large amounts taken.

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body temperature regulation...

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Alcohol causes a dose-related depression of all areas of the CNS. Depression of hypothalamus results in hypothermia.

Acute intoxication can be lethal due to depression of medullary respiratory and CV centers

Stimulation observed after one or two drinks is a result of depression of inhibitory control mechanism of the reticular activating system.

Chronic use can lead to irreversible neurological damage.

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respiration and CV and GI

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Respiratory system:
At about 0.40% - depression of respiratory center results in death

Cardiovascular system:
Moderate amount – peripheral vasodilation causing slight ↓ BP and heat loss. Regular moderate consumption decreases risk of heart disease (↑ HDL, ↓ platelet aggregation).
High dose – myocardial depression
Chronic change – alcoholic cardiomyopathy

GI Tract:
Stomach – at low doses, alcohol stimulates salivary and gastric acid secretion. High concentrations of alcohol (>20%) may inhibit gastric acid secretion and peptic activity.
Intestine – chronic ingestion will lead to ↓ absorption of folic acid, thiamine, niacin, other vitamins, constipation, or diarrhea.
Pancreas – chronic ingestion may lead to pancreatitis

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alcohol and your liver,

and endocrine

and blood

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Liver:
Chronic ingestion → induction of hepatic microsomal enzyme system and other enzyme systems.
Chronic excessive use fatty → infiltration, hepatitis, and hepatic cirrhosis.
Biochemical changes

Endocrine:
Diuretic effect
↓ testosterone
↑ estrogen
↑ corticotropin secretion

Blood:
Anemia
Increased susceptibility to infection

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absorption...

what metabolizes the alcohol in the GI tract?

how about distribution and the air?

does it cross the placenta?

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Absorption
Oral absorption from GI tract by passive diffusion is complete. Peak in 1 hour
Factors influencing rate of absorption – alcohol concentration and food content
Alcohol dehydrogenase in GI tract

Uniform distribution in total body water (40L in 70 kg man). Equilibrates rapidly with alveolar air
Alveolar alcohol concentration is an accurate estimate of blood concentration

Crosses placenta and into milk (primary teratogen in this society)

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metabolism... how much is metabolized.. what order kinetics?

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Metabolism:
90-98% of ethanol ingested is completely oxidized in the body. The rest is excreted via the urine and expired air.

At BAC > 0.01% the metabolism of ethanol follows zero-order kinetics. (about 10g per hour)

Alcohol metabolism is carried out by:
Alcohol dehydrogenase – most important enzyme for in vivo metabolism of ethanol
Microsomal mixed function oxidase system

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What is the limiting factor of alcohol metabolism?

acute effects and treatment

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The alcohol dehydrogenase mediated step is the rate-limiting step. Availability of NAD seems to be the limiting factor. Reduction in availability of NAD also decreases gluconeogenesis, resulting in hypoglycemia.

Excretion: 2% to 10% may be excreted in urine and exhaled air

effects all parts of the cell, including the nucleus.

Acute effects: Hangover effects, tremor, fatigue, headache, nausea, vomiting

Treatment: ibuprofen

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acute intoxication

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Acute intoxication
Severely intoxicated individual is stuporous or comatose, has cold skin, and reduced body temperature, breathes slowly and has decreased heart rate

Treatment: Symptomatic support

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acute intoxication

chronic alcoholism... sx and tx

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Acute intoxication:
Severely intoxicated individual is stuporous or comatose, has cold skin, and reduced body temperature, breathes slowly and has decreased heart rate

Treatment: Symptomatic support

Chronic alcoholism:
Symptoms:
Fatty liver, hepatic cirrhosis, pancreatitis, severe depression, dementia, psychosis, Wernicke-Korsakoff Syndrome, cardiomyopathy, peripheral neuropathy, anemia, increased susceptibility to infection

Treatment:
Vitamin B replenishment, adequate dietary intake, diazepam for management of Wernicke’s Syndrome, disulfiram(?).

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tolerance and dependence...

pharmacokinetic and pharmacodynamic tolerance

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Steady intake of ethanol produces tolerance (but not to lethal effect).

The tolerance consists of both a pharmacokinetic tolerance and a pharmacodynamic tolerance. The pharmacokinetic tolerance (enhanced rate of metabolism) plays a small role.

Both a psychological and physical dependence can occur with chronic alcohol use.

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withdrawal

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Abrupt withdrawal from alcohol may be fatal
Intensity of withdrawal is proportional to degree of physical dependence. Physical dependence proportional to tolerance.

Drug treatment of alcohol withdrawal
Chlordiazepoxide or diazepam for delirium tremens (or lorezepam if you have a concern about liver damage)
Phenytoin for seizures
Other sedative hypnotics and antianxiety agents in case of a significant degree of physical dependence
Diet, vitamins, glucose, fluid, electrolyte replenishment

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Abstinence:

Disulfram MoA (what isn't the MoA)

what can it also be used for?

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Mechanism of action: Inhibition of aldehyde dehydrogenase leads to increase blood levels of acetaldehyde following ingestion of alcohol

Rationale for use: An individual ingesting alcohol while on disulfiram experiences a distinctly unpleasant reaction due to acetaldehyde accumulation. The signs and symptoms of the disulfiram-alcohol interaction begin within 5-10 minutes of alcohol ingestion; lasting for several hours, and include nausea, vomiting, pulsating headache, palpitations, vasodilation, hypotension, hyperventilation.

Contraindication: Severe myocardial disease, psychosis. Patients taking mediation containing alcohol.

May be effective in preventing cocaine relapse.

Mechanism not due to inhibition of aldehyde dehydrogenase.

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Abstinence:
Naltrexone

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Opioid antagonist which blocks the rewarding effects of alcohol. Limitation is possibility of liver damage at high dose

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Abstinence:
Acamprosate (Campral)

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Acamprosate (Campral)
-An anti-craving drug approved by FDA August, 2004. Used to maintain abstinence in former drinkers.
-Blocks NMDA receptors, calcium channels, and activates GABAA receptors. It is uncertain how this decreases craving for alcohol. Company literature suggests that it “balances” GABA and glutamate activity in the brain.

Adverse effects
-Headache, diarrhea, flatulence, and nausea

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ssri and sodium oxybate.. what.

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SSRIs
Relieve underlying depression or anxiety
Sodium oxybate (investigational for treatment of alcohol use)—narcolepsy

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what is the most frequent teratogenic drug

what are the signs.

Fetal alcohol effects

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Alcohol estimated to be most frequent cause of teratogenically induced mental deficiency in western world. While heavy “binge” drinking causes the most severe damage, even modest drinking can be damaging.

Incidence of FAS estimated to be 4-7/100,000 live births

Signs:
-CNS dysfunction (Low IQ; microencephaly)
-Prenatal or postnatal growth retardation
-Cluster of facial abnormalities, limb anomalies, brain and heart anatomical defects

Fetal Alcohol Effect:Also need to consider Fetal Alcohol Effect – less dramatic but may cause behavioral and/or learning problems. As little as one drink per week during pregnancy increases aggressive behavior in the child

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Pharmacokinetic interactions with drugs metabolized via ____

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2 sites

Pharmacokinetic interactions with drugs metabolized via MFO: initial inhibition of their metabolism followed by induction upon chronic use. Liver damage may also affect drug metabolism.

Pharmacodynamic interactions at CNS and other sites. (See attached table)

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Methanol

where do you find it.

oxidized by what into what?

what order kinetics?

how do you treat methanol intoxication?

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Methanol = methyl alcohol = wood alcohol
Industrial solvent, an antifreeze, used as an adulterant to “denature” ethanol used for cleaning purposes; also in sterno, windshield wash liquids.

-Absorption and distribution similar to ethanol
-Methanol is largely oxidized in the body by ADH to formic acid and formaldehyde
-Metabolism zero order but slower than ethanol metabolism
-Ethanol competes with methanol for alcohol dehydrogenase thereby decreasing the rate of methanol oxidation. This competition forms the basis of ethanol’s use in the treatment of methanol intoxication

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sxs of methanol poisoning?

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Symptoms of methanol poisoning:
Methanol poisoning consists of :
Some CNS depression
Slow METABOLIC ACIDOSIS produced by formic acid – major cause of death
A specific damage to retinal cells caused by formaldehyde leading to blindness
4 ml → blindness
80-150 ml → fatal

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Methanol TX

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Treatment
Hemodialysis, support respiration
NaHCO3 administration to correct for metabolic acidosis
Delay methanol metabolism with ethanol or Fomepizol (Antizol) - an inhibitor of alcohol dehydrogenase which decreases metabolism of methanol to toxic metabolites.

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Ethylene Glycol

what kind of kidney stones?

tx?

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Solvent, antifreeze. Sweet taste attracts children and animals.

In large dose may produce alcohol-like depressant syndrome

**Oxidation to glycoaldehyde and oxalate may cause serious metabolic acidosis (anion gap) and renal damage (oxalate crystals).

Fomepizol (Antizol) (inhibitor of alcohol dehydrogenase) decreases metabolism of ethylene glycol to toxic metabolites.

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know the objective about drug interaction

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ok i will.