Alcohols

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Alcohols

• History/Cultural
• Ethanol as a human consumable has existed fro
  8000 years. In Western society beer wine were
  a main staple of daily life until the early 19th
  century, the development of a reliably safe water
  supply ended the public health benefit of beer
  wine consumption over water. In many societies
  alcohol consumption has become a socially
  acceptable form of recreation.

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• 10 of the general population in the US is
  unable to limit their ethanol consumption
  (alcohol abuse). People who continue to drink
  alcohol in spite of adverse medical or social
  consequences directly related to alcohol
  consumption suffer from alcoholism. This
  disorder has both genetic and environmental
  determinants.
• Alcohol consumption frequently interferes with
  diagnosis, treatment and recovery from all forms
  of illness and significantly increases the risk
  of ill health.

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Basic Pharmacology of Ethanol

• Pharmacokinetics
• Ethanol is a small water soluble molecule that is
  rapidly absorbed from the GI tract (stomach vs.
  small intestine). Ingestion in a fasting state
  results in peak concentrations within 30 minutes.
  Distribution is rapid with tissue levels
  approximating blood concentrations.
• For an equivalent dose of ETOH women have a
  higher peak concentration than men women have
  lower total body water content. CNS levels of
  ETOH rise quickly due to the large proportion of
  CO directed at the CNS.
• 90 of ETOH is metabolized in the liver, the
  remainder is excreted through the lungs urine.
  Usual levels of ETOH saturate the metabolic
  pathway so its metabolism follows zero-order
  kinetics. The typical adult can metabolize 7-10g
  of ETOH /hour

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• ETOH is metabolized to acetaldehyde via two
  competing processes.
• 1. Alcohol dehydrogenase pathway.
• This is the primary pathway for ETOH
  metabolism. Mainly found in the liver also in
  the brain stomach. Men have higher levels of
  gastric ADH function than females. The
  accumulation of NADH (excess reducing
  equivalents) in the liver plays a role in liver
  damage seen with chronic ETOH use.
• 2.

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• 2. Microsomal ethanol oxidizing system
• A mixed function oxidase this enzyme complex
  uses NADPH as a cofactor. This complex uses
  cytochrome P450 2E1, 1A2 3A4. At ETOH levels lt
  100mg/dl this system contributes little to ETOH
  metabolism. As levels exceed 100mg/dl this
  complex assumes a significant role in ETOH
  metabolism. Chronic use induces the production
  of this complex. This results in increased ETOH
  metabolism but also increases metabolism of other
  drugs oxidized via this pathway.

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• 3. Acetaldehyde metabolism
• Acetaldehyde is oxidized in the liver via
  mitochondrial NAD-dependent aldehyde
  dehydrogenase (ALDH). Acetate is further
  metabolized to CO2 and water.
• Some ethnic groups (especially Asians) have
  variations in ADH efficiency marked slowing ETOH
  metabolism (increased risk for alcoholism) and
  variants of ALDH with reduced activity resulting
  in increased acetaldehyde (decreased risk of
  alcoholism).

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• (a) The constitutive alcohol dehydrogenase (ADH)
  pathway produces acetaldehyde that is further
  metabolized by aldehyde dehydrogenase (ALDH).
  Decreased ALDH activity in individuals with
  low-activity version of ALDH, as well as block of
  ALDH by drugs such as disulphiram is associated
  with acetaldehyde accumulation and aversive
  reactions to EtOH ingestion. The competitive
  blocker of the most abundant forms of ADH,
  fomepizole, is now used (instead of EtOH) to aid
  in the management of methanol and ethylene glycol
  poisoning by slowing the conversion of methanol
  and ethylene glycol into their highly toxic
  metabolites. (b) The inducible microsomal
  ethanol-oxidizing system (MEOS) utilizes the
  cytochrome P450 system to convert EtOH into
  acetaldehyde. After chronic alcohol consumption,
  the activity of this system increases due to a
  rise in, especially, the CYP2E1 isoform, of
  cytochrome P450. The upregulation of this system
  contributes to alcohol tolerance, and it is
  likely that oxidative stress associated with the
  activation of the MEOS makes an important
  contribution to alcohol-induced liver damage.

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• Acetaldehyde is an active metabolite with a range
  of toxic and pharmacological effects, and many of
  the effects induced by direct acetaldehyde
  application mimic those of ethanol. In
  particular, administration of low doses of
  acetaldehyde to the brain produces behavioral
  effects that are typical of addictive drugs, such
  as psychostimulation and reinforcement. In
  contrast, accumulation of high acetaldehyde
  levels in the periphery leads to a strong alcohol
  aversion and prevents further alcohol drinking.
• The contribution of such acetaldehyde-induced
  effects to the overall effects of alcohol
  consumption under normal physiological conditions
  still is controversial. The main issue in these
  discussions is the acetaldehyde concentration
  that typically is achieved after alcohol
  consumption in vivo, under normal physiological
  conditions. Nevertheless, studies involving
  alteration of catalase activity provide, despite
  their obvious weaknesses, converging evidence
  that acetaldehyde contributes to various
  behavioral effects of ethanol, especially its
  stimulant properties.

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• Some ethnic groups (especially Asians) have
  variations in ADH efficiency marked slowing ETOH
  metabolism (increased risk for alcoholism) and
  variants of ALDH with reduced activity resulting
  in increased acetaldehyde (decreased risk of
  alcoholism).

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Pharmacodynamics of Acute Ethanol Consumption

• 1. Central Nervous System
• At low levels ETOH causes mild sedation, relief
  of anxiety and mild disinhibition. At higher
  concentrations speech is slurred, ataxia
  develops, judgment is impaired and marked
  disinhibition occurs. CNS effects are more
  marked as the blood level is rising due to acute
  tolerance. Chronic ETOH use requires a much
  higher ETOH levels to elicit the same effects. At
  higher levels ETOH suppresses cortical function
  (coma) and medullary respiratory centers (apnea)
  leading to death.

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• Pharmacodynamics ETOH affects a large number of
  membrane proteins that are involved in a wide
  variety of neurotransmitters (amino acids, ions,
  opioids, etc.). The main affect appears to
  involve glutamate and GABA pathways. ETOH
  enhances the action of GABA receptors
  (inhibitory) and inhibits the ability of
  glutamate to open a subset of ion channels
  associated with NMDA receptors (N-methyl-D-asparta
  te). These pathways are involved in memory and
  learning (alcoholic blackouts).

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BAC Clinical Effects in Nontolerant Individuals
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• 2. Heart
• Significant depression of myocardial
  contractility occurs in individuals acutely
  consuming moderate amounts of ETOH gt100mg/dl.
• 3. Smooth muscle
• ETOH is a vasodilator via central vasomotor
  depression and the direct relaxation caused by
  acetaldehyde. Hypothermia is exacerbated.

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Consequences of Chronic Alcohol Consumption

• The tissue damage caused by chronic ETOH
  consumption is due to a combination of the
  direct metabolic effects of ETOH and the
  metabolic consequences of producing large amounts
  of metabolically active substances. Mechanisms
  implicated in tissue damage include increased
  oxidative stress, glutathione depletion,
  mitochondrial injury, growth factor dysregulation
  and the potentiation of cytokine induced injury.

Risk of Cirrhosis of the Liver ETOH consumption
?
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• 1. Liver Gastrointestinal Tract The risk of
  developing liver disease is related to the
  average amount of daily consumption and the
  duration of use. Women appear more susceptible
  to hepatotoxity than men. Concurrent infection
  with hepatitis increases the risk of severe liver
  disease. Hepatotoxicity is related to the
  effects of metabolic oxidation, dysregulation of
  fatty acid oxidation, activation of the immune
  system due to ethanol and its metabolites.
  Bacterial endotoxins (increased due to intestinal
  pathology associated with ETOH) are directly
  hepatotoxic and elicit the production of
  tumor-necrosis factor. ETOH is the most common
  cause of chronic pancreatitis. Gastritis with
  chronic blood loss often accompanies ETOH abuse
  and promotes anemia and protein malnutrition.

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• 2. Nervous System
• Tolerance physical dependence Consumption of
  large amounts of ETOH over prolonged periods of
  time elicit tolerance and physical
  psychological dependence. Tolerance to the
  respiratory effects of ETOH is limited, even with
  chronic use the lethal blood level remains at
  most 600mg/dl. With abstinence or reduction in
  intake a withdrawal syndrome will develop. Mild
  withdrawal symptoms are agitation, tremulousness,
  psychosis and seizures. Delirium tremens
  indicates severe tolerance and has a significant
  risk of morbidity. Psychological dependence
  likely involves local effects on concentrations
  of serotonin, opioids and dopamine the
  neurotransmitters involved in reward neural
  circuits.

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• 2. Nervous System
• Neurotoxicity Consumption of large amounts of
  ETOH for extended periods (years) often results
  in neurologic deficits
• Generalized symmetric peripheral nerve injury,
  usually presenting as distal extremity
  paresthias.
• Gait disturbances related to cerebellar vermian
  degeneration
• Dementia
• Demyelinating disease
• Wernickke-Korsakoff syndrome- EOM paralysis,
  ataxia confusion (confabulation). Untreated
  this can progress to coma death. It is caused
  by thiamin deficiency and responds promptly to
  thiamin administration. Unfortunately the memory
  deficit remains (Korsakoffs psychosis).

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• Cardiovascular System
• Cardiomyopathy heart failure Heavy, prolonged
  consumption is associated with a dilated
  cardiomyopathy with ventricular hypertrophy and
  fibrosis. The most common non-ischemic cause of
  CM, reversible with abstinence. Direct myocyte
  toxicity and free radical damage are implicated.
  Ethanol appears to interfere with the therapeutic
  effects of beta-blockers and ACE inhibitors used
  to treat this disorder idiopathic dilated
  cardiomyopathy responds well to these
  interventions.
• Arrhythmias Both chronic acute (binge)
  drinking are associated with atrial ventricular
  arrhythmias due to abnormalities of K, Ca2
  and/or Mg2 metabolism. Often seen during acute
  withdrawal, arrthymias may cause seizures,
  syncope and sudden death.

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• 3. Hypertension Consumption of 3 or more
  alcoholic beverages per day is associated with
  hypertension this is though to be responsible
  for 5 hypertensives making ETOH the most common
  remediable cause of hypertension. Cessation of
  ETOH intake results in lowering BP, ETOH induced
  hypertension also responds to pharmacotherapy.
• 4. Coronary heart disease A number of
  observational studies have identified moderate
  ETOH consumption (1-2/day for men, 1/day for
  women) association with decreased risk of
  cardiovascular events mediated through elevated
  HDL cholesterol, anti-inflammatory effects and
  anti-oxidants.
• 5. Blood ETOH consumption impairs hematopoiesis
  via alcohol related folate deficiency, chronic
  low grade GI hemorrhage, associated vitamin
  deficiencies and malnutrition contribute to
  anemia ETOH may directly impair hematopoiesis.

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Other Effects

• Endocrine/Electorlyte Balance Hypoglycemia and
  ketosis due to hepatic dysfunction occurs with
  prolonged ETOH consumption. Electrolyte
  disorders due to deranged aldosterone secretion
  and periodic emesis are common.
• Fetal Alcohol Syndrome ETOH rapidly crosses the
  placenta and achieves maternal blood levels in
  the fetus fetal liver lacks alcohol
  dehydrogenase activity and so is dependent on
  maternal metabolism. FAS requires a significant
  exposure to produce the classic clinical
  presentation (IU growth retardation,
  microcephaly, intellectual impairment,
  dyscoordination, facial malformations, joint
  anomalies), of more concern is evidence that even
  minimal exposure to ETOH may produce subtle but
  debilitating CNS effects (Fetal Alcohol Effect).
  In animal models ETOH triggers neural apoptosis
  and aberrant neuronal and glial migration.

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• 3. Immune System ETOH appears to elicit a
  hyperactive immune response in the liver
  pancreas (Kupffer cell hyperactivity, increased
  cytokine production) while suppressing immune
  function in the lung (suppression of alveolar
  macrophages, inhibition of chemotaxis, impaired
  T-cell function). Chronic alcohol use produces an
  overall immune suppression leading to poorer
  prognosis with infectious diseases particularly
  pneumonia.
• 4. Carcinogenesis There is an increased risk
  for cancers of the mouth, pharynx, larynx,
  esophagus, liver and lung. There is a small
  increased risk of breast cancer. While ETOH is
  not directly carcinogenic its metabolite
  acetaldehyde can damage DNA as can the oxygen
  radicals produced by increased cytochrome P450
  activity.

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• Alcohol-Drug Interactions ETOH induced
  increases in drug metabolizing enzymes account
  for the majority of drug-ETOH interactions. This
  is particularly important for acetaminophen
  chronic consumption of 3 or more drinks per day
  significantly increases the risk of
  hepatotoxicity through the generation of toxic
  metabolites. Acute intoxication may impair the
  metabolism of a number of drugs
  (sedative-hypnotics, TCAs, psychotropics). It
  potentiates the effects of many vasodilators and
  oral hypoglycemics

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BAC Calculator

• The metabolic pathway for ETOH saturates at very
  low levels of ETOH
• Metaboilsm is 1st order only at low
  concentrations
• As levels increase metabolism becomes 0 order
  (linear).