Pharmacology Joseph Cordova
September 1 8:00am Jody Haigood
Dr. Syapin
Pharmacology of Alcohols
1. Ethyl Alcohol (Ethanol; “Alcohol”)
A. Alcohol use and medicine
1. As a physician you might recommend occasional alcohol to patients. Alcohol has a huge impact on medicine. It is estimated that 40% of patients in the hospital are there because of alcohol.
2. Chronic heavy use of alcohol elevates the risk of premature death 3-fold
a. moderate drinking - 4 drinks a day? 4 drinks a week? (People have different interpretations)
b. heavy drinking -5 or more drinks a day
c. binge drinking
B. Absorption and distribution
1. Ethanol is readily absorbed orally
a. Most of absorption takes place in the GI tract , then distributed throughout the body
b. rate of absorption is influenced by contents of the stomach and also the concentration of the alcohol, food delays the rate of absorption as does higher alcohol concentrations
c. Peak blood level of alcohol is reached from 30-90 min. after a drink
2. Ethanol is distributed in total body water - lipophilic and hydrophilic properties
a. crosses membrane barriers easily - crosses placenta to affect fetus
b. appears in breast milk
C. Metabolism
1. Metabolism of ethanol follows zero-order kinetics
a. some alcohol not metabolized—basis of breathalyzer test as some is excreted through the lungs or urine. There is a strong correlation between the blood concentration and the concentration in a person’s breath.
b. most of the metabolism takes place in the liver
2. Rate limiting step is oxidation of ethanol to acetaldehyde by alcohol dehydrogenase (ADH)
a. continued ethanol use also activates the P4502E1 enzyme, metabolizes many other drugs and can lead to the basis of interactions between acetaminophen and alcohol
b. ADH converts ethanol to acetaldehyde, which requires NAD and produces NADH. The body does not like acetaldehyde, so it is very quickly converted to acetate by ALDH (type 2). This conversion also requires NAD and produces NADH. Therefore, the metabolism of ethanol produces a lot of NADH.
c. ALDH has different isoforms. ALDH22 is genetically dominant, yet it is inactive and breaks down acetaldehyde inefficiently. Acetaldehyde build-up causes nausea/vomiting, flushing (i.e., red face) due to vasodilation. But people with ALDH22 very rarely have problems with alcohol (i.e., low incidence of alcoholism).
D. Physiological changes due to ethanol metabolism resulting from increased NADH/NAD ratio in liver. It changes the metabolism of other substances in the liver.
1. Hyperlacticacidemia by producing lactate rather than pyruvate.
2. Hyperuricemia
3. Hypoglycemia
4. Hyperlipidemia
5. Ketosis
(Ethanol does not directly affect the enzymes involved. The effects are due to cofactor changes, NADH/NAD ratio. He said that this is often a test question)
E. Pharmacological effects
1. Acute effects on the CNS
a. ethanol is a very weak drug acting at mM concentrations
b. ethanol is a general CNS depressant producing intoxication
1. ethanol first alters mood, cognitive ability, and fine motor skills then reduced visual acuity, slurred speech, irritability, and sedation can occur
c. CNS effects are dependent on the BEC, a direct reflection of drug at its site of action
in brain
1. acute tolerance- Mellanby effect is acute tolerance occurring during a single ethanol exposure. If no tolerance occurs with a drug it should have the same effect at the same blood level across time. Take a patient and measure the eye function across time after giving a fixed dose of ethanol. If the blood level increases, you get an increase in your measurement. Nystagmus will occur while the BEC is rising, but what happens is nystagmus will disappear at a higher blood level than what first occurred when BEC is decreasing. The difference is due to the CNS having an acute tolerance. It can now function more normally at a higher blood level.
2. metabolic tolerance by induction of the P4502E1 enzyme
3. state dependent and independent tolerance
2. Chronic effects on the CNS
a. chronic drinking elicits neuroadaptive changes in CNS
1. it inhibits thermal regulation and contributes to death from overdose of ethanol. Body temp becomes what the ambient temp is (pokiothermic)
2. it inhibits testosterone production
3. CNS tolerance can occur. (This is not a metabolic tolerance). Patient can present appearing normal and have a very high BEC.
b. physical dependence can occur- take away drug and get withdrawal
3. Cardiovascular system
a. good effects -reduced incidence and mortality from coronary heart disease-with moderate or low alcohol intake (1 or 2 drinks a day). Current recommendation though is to not advise someone who does not drink to start - could increase risk of complications (including alcoholism). This is not a case though of 2 glasses is good so 4 must be better.
b. problem drinking associated with cardiovascular dysfunction
4. Gastrointestinal system
a. low alcohol intake stimulates gastric secretion
b. chronic use may cause gastritis
c. high alcohol intake inhibits gastric secretions and motility and increases absorption of alcohol and irritates the GI mucosa
5. Liver
a. acute intake has few direct effects
b. chronic intake can cause fatty liver that can lead to cirrhosis. There is some linking evidence of alcohol cirrhosis and hepatic encephalopathy. There is also a susceptibility to the hepatitis C virus (However, the virus might produce the cirrhosis – not yet solved).
F. Ethanol’s mechanisms of action (how it causes intoxication)
1. Intoxication
a. intoxication is not due to ethanol disrupting plasma membrane fluidity of brain cells
b. current belief is ethanol acts at hydrophobic sites on brain proteins to cause acute intoxication (neurotransmitter systems)
1. GABA A system inhibits neural activity and ethanol enhances GABA activity
2. Ethanol inhibits NMDA (glutamate type receptors) which is involved in stimulation of CNS
II. Chronic Changes
A. Neuroendocrine
1. Arginine- vasopressin system (at least in animals) seems to be involved in the CNS tolerance that develops. Can give animal alcohol, they become tolerant, inject vasopressin in brain, remove alcohol, and the tolerance will still be there.
2. Calcium channels are also important in physical dependence or at least the withdrawal dependence.
3. Alcohol is toxic- An overdose can lead to seizure, coma, respiratory depression, cirrhosis, brain damage, and teratogen.
a. cirrhosis reduces liver function
b. brain- ventricular system enlarged in alcoholics due to brain shrinking and loss of brain matter. There is a lot is white matter loss and glial cell loss. Abstinence can get some reversal but never back to normal.
c. Fetal Alcohol Syndrome- there are morphological and CNS effects. Smaller head circumference, smaller brain, low IQs. Mental retardation is a problem.
B. Drug Interactions- Take home message is that alcohol interacts with lots of drugs. Be aware of patient’s alcohol intake.
1. Anesthetics are CNS depressants; alcoholics notorious for being “hard to put down” for surgeries
2. Anxiolytics (benzodiazepines)
3. Hypoglycemics
C. Drugs that alter effects of alcohol
1. Naloxone and Camposate – may be used to prevent alcoholics from relapsing after they have been through detox.
2. Disulfiram inhibits ALDH enzymes. It is used in detox by allowing acetaldehyde buildup and they feel horrible- nausea/vomiting. High levels can be dangerous.
D. Contraindications
1. Ulcers
2. Hepatic disease
3. Myopathies (cardiac or skeletal)
4. Pregnant women
E. Therapeutic uses
1. solvent – example is NyQuil
2. rubbing compound
3. disinfectant
4. antidote for methanol or ethylene glycol poisoning. Methanol is metabolized by the same enzymes. It has zero order metabolism but it is slower so you can outcompete it using ethanol. Methanol goes to formaldehyde, which can have effects on optic system, then formic acid which causes acidosis.
Other Drugs
1. Isopropyl alcohol-ethanol does not work as antidote. Dialysis is the only useful method to get rid of isopropyl alcohol.
2. Ethylene glycol (anti-freeze) is metabolized by ADH system. Ethanol can be used as an antidote.