Alcohol & Interactions

Sept 2006

Dr B Russell

Dose effect

Doses ~0.5-1 g/kg with 40-50 g doses common cf. mg doses. Tmax ~ 30-90 minutes, absorption from stomach, majority from small intestine due to greater surface area. 5-10% excreted by breath, skin and urine 8-10 g/hr of ethanol metabolized Mellanby effect….. Bioavailability - females 90% v’s males 75%, less gastric alcohol dehydrogenase activity in females

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Training and experience
Memory concentration, insight dulled then lost. Confident, expansive, vivacious, mood swings Acute use  latency to sleep and REM sleep
 in sleep latency disappears with 3 or more nights of

ingestion

Dose dependent effects –  calming, sleep, unconsciousness, surgical anaesthesia, coma, fatal depression respiratory of & cardiovascular

Intoxication - cessation of g/i motor and secretory motor functions so get pylorospasm and vomiting. Can occur independently from local reflex irritation.

CNS effects

Initially - fluidization of lipid membrane bi-layer. Chronic use/alterations to the membrane structure and increasing rigidity. Enhances GABA mediated synaptic inhibition similar to benzodiazepines (flumazenil can reverse CNS depressant effects of EtOH) Inhibits Ca2+ entry/NMDA glutamate channels Antagonism of excitatory amino acid receptors Up-regulation of NMDA receptors and down regulation of GABAA receptors contributes to EtOHinduced withdrawal seizures

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Mesolimbic dopaminergic system

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 impulsivity - disinhibition of the mesolimbic dopaminergic neurons  [circulating monoamines] Evidence of DA-independent mediated reward via the GABAA receptor (significant role modulating endogenous stress) Enhances nicotine’s excitatory effects by activation of nicotinic ACh and 5-HT3 receptors

“Other” effects
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Cutaneous vasodilatation, central effect  salivary, gastric & pancreatic secretions  diuresis – inhibition of ADH and tubular absorption  ACTH release from anterior pituitary  testicular steroid synthesis - hypogonadism and feminization

Hepatic Metabolism
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First pass effect minimal (enzyme overload) Zero-order kinetics, 95% metabolised by the liver, rate determined by availability of NAD+

Disulfram

aldehyde de-hydrogenase inhibitor   acetaldehyde conc. (5-10x) in plasma when taken before or after alcohol

Interacts irreversibly with sulphydryl groups in the cytosolic and mitochondrial forms of the enzyme
Enzyme recovery dependent on synthesis of new enzymes

Disulfram - physical effects

5-10 minutes - cutaneous vasodilatation intense throbbing headache and neck.

Respiratory difficulties, nausea, vomiting, sweating, thirst, chest pain, weakness, blurred vision and confusion.
7 mL mild symptoms, lasting ~30-180 min. Interact with most enzymes containing sulphydryl groups e.g. phenytoin & benzodiazepines. 80% rapidly absorbed.

Alcohol/drug interactions

ACE inhibitors, Angiotensin II inhibitors, Beta blockers, Ca channel blockers, clonidine, diazoxide, diuretics, methyl dopa, nitrates, vasodilator (e.g. hydralazine) enhanced antihypertensive effect Metronidazole, tinidazole – disulfram effect Antidiabetics, alcohol enhances the hypoglycaemic effect and increases the risk of lactic acidosis with metformin

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Antidepressants (SSRIs & TCAs), antipsychotics, antihistamines, bromocriptine, muscle relaxants e.g. baclofen, anticonvulsants, barbiturates, anxiolytics, hypnotics Lowered seizure threshold…………. Opiates – hypotensive and sedative effect

Question – antidiabetics & hypoglycaemia
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Exacerbation of hypoglycaemia by EtOH not fully understood. It is known that if hypoglycaemia occurs when glycogen stores are low the liver turns to formation of new glucose from amino acids (neoglucogenesis) which are released into circulation. Neoglucogenesis is inhibited by alcohol so, the fall in blood glucose may not be prevented and hypoglycaemia can result. EtOH is metabolized by a SEVERAL pathways such as CYP3A4 which is responsible for the metabolism of the sulfonylureas interference could  their effective half-life and  hypoglycemic effect. EtOH also metabolised by CYP2E1 resulting in a significant release of free radicals and energy which, in turn, diminishes reduced glutathione (GSH). Review - Lieber CS. Drug Metab Rev. 2004 Oct;36(3-4):511-29

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