ethanol

ethanol (alcohol and alcohol withdrawal)

see also:

Introduction

  • ethanol is primarily a CNS depressant acting by stimulating GABAA receptor in the CNS.
  • from 1996-2005 throughout Australia, each year, an average of over 80,000 were hospitalised, and over 3,000 died from alcohol attributable injury and disease caused by risky/high risk drinking - mainly due to alcohol dependence, falls, assaults and alcohol abuse1)
  • current advice suggests no more than 2 glasses alcohol per day long term, and no more than 4 glasses alcohol on any one occasion.
  • middle aged men who drink more than 3 standard drinks a day have faster cognitive decline with age, speeding up memory loss by up to 6 years 2)

Pharmacokinetics

  • rapidly absorbed, peak 30-90min from time of last drink, delayed with food
  • initial “overshoot” as distrib. to brain before muscle - minimised by exercise;
  • uniformly distributed in all body tissues Vd=0.6-0.9L/kg (0.1 less in females);
  • air:blood part. coeff. 2100:1 (ie. same amount in 2100ml air if 5.26% CO2 → 216mg CO2 as 1ml blood) & after taking into account the decreased resp. quotient due to alcohol ingestion, thus the amount ethanol accompanying 190ml exp. CO2 = that in 1ml blood;
  • 90-98% oxidised by liver cytosol alcohol dehydrogenase (Km=7.4mg/dl) using NAD ⇒ acetaldehyde which is converted via aldehyde dehydrogenase to acetyl CoA.
    • genetic polymorphism of both alcohol & aldehyde dehydrogenase;
    • NB. up to 25% metab. by hep. microsomal NADPH/cytoch.P450 oxidising system which may be induced 5-fold by chronic intake → 2x overall increase in ethanol metabolism rate;
  • rate of elimination: 80-150mg/kg b.wt/hr with mean of 100 (= 7g/hr in 70kg man)

Tolerance

Metabolic

  • induction of microsomal system → 2x elimination rate;

Pharmacodynamic tolerance

acute:
  • effects greater in rising than falling or constant level phase;
  • diuretic effect, CNS “intoxication”;
  • cross-tolerance occurs (see below);
chronic:
  • ? behaviourally augmented tolerance - a learned ability to cope;
  • mainly for low doses only; higher doses near lethal range no tolerance!
  • cross-tolerance occurs to CNS depressants;

Acute actions

CNS effects

  • 1st effects those processes that depend on training & previous experience & that usually make for sobriety & self-restraint.
  • Memory, concentration & insight are dulled & then lost;
  • confidence abounds, personality ⇒ expansive & vivacious;
  • uncontrolled mood swings & emotional outbursts may occur;
  • sensory & motor disturbances ⇒ sedation with resp. depression;
  • effects are generally proportional to blood [ethanol] but greater when rising than falling;

acute toxicity

CNS effects
  • (cortical then limbic then cerebellar & finally brain stem):
    • [ ] < 0.02%
      • ⇒ euphoria, some disorder of cognitive & motor function
      • ⇒ disinhibition and increased sexual desire (but impaired sexual responsiveness)
      • ⇒ decreased seizure threshold
      • ⇒ inhibition of ADH release in proportion to [ethanol]
        • (but only when it is [ethanol] is rising!) → diuresis
    • [ ] > 0.2%
      • ⇒ cerebellar ataxia, memory impairment
      • ⇒ narcosis, decreased CO2 drive
        • ⇒ risk of mononeuropathy due to prolonged nerve compression
    • [ ] > 0.3-0.4%
      • ⇒ risk of coma & fatal respiratory arrest
CVS effects:
  • vasodilatation (unless severe intoxication affecting vasomotor centre)
    • ⇒ hypothermia, mild hypotension
  • increased exercise-induced angina if IHD
Other acute toxicity effects:
  • increased adrenal medulla catecholamine release
    • ⇒ hyperglycaemia, pupillary dilatation, slight increase BP;
  • increased gastric secretions & irritative to mucosa if 40% alcohol
    • ⇒ increased risk peptic ulceration
  • acute fatty liver within a few days of even modest alcohol consumption
  • acute hepatitis +/- steatorrhoea in bouts of heavy drinking:
    • most cases are probably subclinical
    • spectrum ranges from minimal nausea, vomiting & abdo. pain to acute liver failure
      • ⇒ tachycardia, fever, hypotension, RUQ tenderness, +/- jaundice
      • ⇒ LFT's: elevated AST, ALT usually < 10x normal with ALT < AST
      • ⇒ FBE: neutrophilia of 10000-20000 common
      • check PT, U&E, acid-base for alcoholic ketoacidosis, deranged electrolytes & liver dysfunction
      • may need to exclude viral hepatitis, pancreatitis, gastritis, CBD obstruction (see hepatobiliary imaging)
    • Mx is primarily supportive:
      • correct fluid & electrolyte imbalance
      • antiemetics
      • watch for & Rx hypoglycaemia
      • give thiamine 100mg IV BEFORE any glucose to avoid inducing acute Wernicke's enceph.
      • give empirical magnesium replacement Rx unless C/I by renal failure or known hypermagnesaemia
      • high-calorie, vitamin supplemented diet
      • restrict protein if evidence of cirrhosis or incipient encephalopathy
      • H2 antagonists &/or antacids to Rx coexisting gastritis
      • look for & Rx GIT bleeding
      • admission to hospital generally NOT required unless concern over:
        • degree of fluid & electrolyte abnormality
        • ability to retain oral intake
        • coexistent diagnoses/complications
        • patient's social situation
  • acute fiber rhabdomyolysis

Chronic use toxicity

  • Liver:
    • fatty change (steatosis) most likely due to diminished NAD+/NADH ratio which favors TG production
      • direct function of the duration & amount of alcohol consumed
      • in general, is reversible with cessation of alcohol
      • ⇒ benign, usually painless hepatomegaly
    • alcoholic cirrhosis
      • ⇒ portal hypertension → oesophageal varices
      • ⇒ hypoalbuminaemia → oedema & ascites
      • ⇒ impaired production of clotting factors
      • ⇒ impaired metabolism of drugs
  • CNS:
    • ? cerebral atrophy
    • Korsakoff's encephalopathy - memory impairment, confabulation
    • adolescent alcohol intoxication gives ~5x risk of young onset dementia in men (median age onset 54yrs), this increases to 20x risk if combined with 2 other risk factors such as depression, antipsychotic use, substance abuse, FH father with dementia, or being in lower 1/3rd percentiles for cognition or height.3)
  • Heart:
    • irreversible congestive cardiomyopathy
  • Sk.muscle:
    • chronic fiber rhabdomyolysis → myopathy
  • Testes:
    • atrophy → sterility
    • decreased testosterone production, increased metabolism, & increased oestrogen production → gynaecomastia, impotence
  • Pancreas:
    • chronic pancreatitis
  • GIT:
    • peptic ulceration
    • constipation or diarrhoea
    • impaired absorption esp. of thiamine
  • Blood:
    • sideroblastic & megaloblastic anaemia; thrombocytopenia;
    • decr. leukocyte migration → decr. inflamm. response to infection;
  • Thiamine or other nutritional deficiency (due to poor food intake & impaired absorption):
    • CNS:
      • Wernicke's encephalopathy - ataxia, confusion, ophthalmoplegia
      • cerebellar degeneration
    • PNS:
      • peripheral neuropathy - demyelination
ethanol.txt · Last modified: 2014/01/10 00:15 by gary1