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ETHANOL
Júlia Timár
2008
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SELF-ADMINISTRATION
positive
negative
equal
unequal
continousincrease
Opioidos
Ethanol
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GABAA receptors
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NMDA receptors
ethanol
decrease of the NMDA-stimulated DA release
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Ethanol dependence
Ethanol intoxication
? NMDA ()
? NMDA ()
? voltage-sensitive Ca2-channels ()
? voltage-sensitive Ca2-channels ()
? GABAA (-)
? GABAA (-)
output ???
output ????
Weight, F.F. Lovinger, D.M., White, G. and
Peoples, R.W. (1991) Ann. Ny. Acad. Sci. 625,
97-107 Brennan, C.H., Guppy, L.J. and Littleton,
J.M. (1989) Ann. Ny Acad. Sci. 560, 467-469.
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EFFECT of ACUTE ETHANOL
cation chanel
5 HT3 receptor
nicotinic Ach receptor

• enhanced action of 5-HT and acetylcholine

• activation of cation channels

output ??
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EFFECT of ETHANOL on the 5-HT-ergic SYSTEM
acute increase of 5-HT function
chronic gradual decrease of 5-HT function
at withdrawal decrased 5-HT- ergic function
?
alcohol craving
alcoholists corrects the serotonergic
hypofunction by self-medication
hypothesis of Tabakoff és Hoffman (1991)
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Pharmacokinetic parameters of ethanol
absorption topically - weak orally complete
(from the stomach)
distribution in the whole body Vd - 68 of the
body weight in man 55 in women
metabolism gt90 is metabolised O order
kinetic 100 mg/kg/hour (0,015/hour)
enzyme-induction, hepatic disease affects it
excretion lung, kidney, breast milk, perspiration
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METABOLISM of ETHANOL
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EthanolCH3CH2OH
NADPH O2
NAD
Alcohol dehydrogenase
MEOS
NADPH
NADH
AcetaldehydeCH3CHO
NAD
Aldehyde dehydrogenase
NADH

• in case of hihger ethanol concentation
  activity of MEOS increases

AcetateCH3COO-

• in chronic alcoholists activity of MEOS
  increases

MEOSmicrosomal ethanol-oxidizingsystem
ethanol clearence increases
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ACUTE ETHANOL INTOXICATION I
Phase of excitation 0.5-1.5 increased
blood flow of the skin (flush) increased
respiration increased motor activity lack of
inhibitions agressivity
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ACUTE ETHANOL INTOXICATION II
Phase of depression 1.2-2.5
stupor sleepiness (falling asleep with
ease, awakening with ease) symptoms of
deficiency in walking, in
speech perception disorders slow, impeded
reactions
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ACUTE ETHANOL INTOXICATION III
Narcosis gt 2.5 deep sleeping
unconsciousness superficial respiration,
respiratory depression dilated pupils
(usually) areflexia
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ACUTE ETHANOL INTOXICATION IV
Asphyxia 4 shock loss of
thermoregulation respiratory stop death
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OTHER EFFECTS
Effects on the heart
myocardial contractivity ?
Effects on the smooth muscle
vasodilation
(CNS effect and acetaldehyde-induced direct
effect)
Effects on the uterus
relaxation
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Consequences of chronic ethanol consumption I
liver alcoholic fatty liver (reversible) alcoholi
c hepatitis cirrhosis
pancreas chronic pancreatitis
GI gastritis anaemia, protein
malnutrition diarrhea
vitamine deficiencies
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Consequences of chronic ethanol consumption II
neurotixicity generalised symmetric peripherial
nerve
injury ataxia
dementia Wernicke - Korsakoff
syndrome (B1 deficiency)
cardiovascular system dilated
cardiomyopathy with ventricular
hypertrophy and fibrosis
arrhytmias (at withdrawal
also!) hypertension
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Consequences of chronic ethanol consumption III

• secondary aldosteronism

• hypoglycaemia (rare)

• increased risk of infection

• increased risk of cancer (mouth,
  esophagus, liver) ?

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Fetal alcohol syndrome
(alcohol abuse during pregnancy)
intrauterin growing ?
microcephaly
poor coordination
flattened face
in very serious cases congenital heart defect
mental retardation
apoptotic neurodegeneration
abnormal neuronal and glial migration
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Tolerance (relatively moderate to the lethal
dose ! )
Physic dependence
Physical dependence withdrawal symptoms depend
on

• daily dose
• frequency of consumption
• period of chronic alcohol consumption

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ALCOHOL WITHDRAWAL SYMPTOMS I
insomnia anxiety tremor (moderate) nausea
more marked tremorincreased intensity of
the starting symptoms sweatingmuscle
crampsvomitinghyperreflexiahypertension,
orthostatic hypotensionnightmaresEEG
symptoms(hallucination)
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ALCOHOL WITHDRAWAL SYMPTOMS II
desorientationagitationdeliriumhyperthermia
acute cardiovascular collapse
persistent hallucinationparanoiaconvulsion
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COMPARISON of WITHDRAWAL SYMPTOMSof OPIOIDS and
DEPRESSANTS(similarities)
OPIOID
ETHANOL anxiely, dysphoria anxiely,
dysphoriacraving cravinginsomnia insomnianausea
, vomiting nausea, vomitinghyperpyrexia hyperpyre
xia
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COMPARISON of WITHDRAWAL SYMPTOMSof OPIOIDS and
DEPRESSANTS(differences)
OPIOID ETHANOL
lacrimation, nasal discharge tremoryawing
hyperreflexiapiloerection deliriumsweatening
seizuresmydriasisabdominal pain tachicardia,
hypertension involuntary movements
DEATH
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TREATMENT OF DELIRIUM TREMENS I

• clomethiazol i.v. infusion (risk of
  respiratory depression)

• benzodiazepines (substitutional therapy)

• B1 vitamine (infusion 500 mg)

• fluid replacement

• balance of electrolites (K, Mg, P)

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TREATMENT OF DELIRIUM TREMENS II

• osmotherapy (prophylactic treatment of edema)

• neuroleptics (tiapride, haloperidol)

• antibiotics

• prophylactic treatment of arrhytmia

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DRUG INTERACTIONS with ALCOHOL
ADDITION of CENTRAL EFFECTS
sedative - hypnotics, anxyolitics
anticonvulsants, antidepressants,
ALCOHOL CHANGES the METABOLISM of
phenytoine, tolbutamide, etc.
acetaminophen risk of hepatotoxicity
HYPOGLYCEMIA in diabetic patients
UNUSUAL ADVERSE EFFECTS with
metronidazole, cephalosporines, oral
antidiabetics, (inhibition of aldehyd
dehydrogenase)
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Therapeutical usage of Ethanol

• decrease of body temperature

(topical)

• antiseptic

• irreversible nerve-blockade (injection)

• anxyoliytic

• appetite enhancer

• methanol and ethylenglycol intoxication

• premature labour

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THERAPY of ALCOHOLISM I
EthanolCH3CH2OH
NADPH O2
NAD
Alcohol dehydrogenase
MEOS
NADPH
NADH
AcetaldehydeCH3CHO
NAD
Aldehyde dehydrogenase
NADH
AcetateCH3COO-
Disulfiram
MEOS microsomal ethanol-oxidizing system
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THERAPY of ALCOHOLISM I
DISULFIRAM
usual dose 250 mg/day in the evening
inhibition of acetylaldehyddehidrogenase
Symptoms in case of alcohol consumption nausea,
vomiting tachicardya headache, migraine,
dizziness dyspnoe collapse
Contraindicated in diabetes mellitus angina
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THERAPY of ALCOHOLIC PATIENS II
(drugs used for preventing the relapse in
alcoholic patients)
Opioid antagonists
Naltrexone
usual dose 50 mg/day
Nalmafene
usual dose 25 mg/day
only after detoxification ( for 3
months)
Gamma-hydroxibutyric acid
for treatment of acute withdrawal symptoms (for 7
days)
??????
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THERAPY of ALCOHOLIC PATIENS III
ACAMPROSATE (Ca acetyl- homotaurinate)
usual dose 3 X 600 mg/day

• increases the number of GABA binding sites in
  animal experiments

• decreases the EAA transmitter function in
  animal experiments

• acts first of all on the central
  withdrawal symptoms (tremor, anxiety)

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Blocking the cascade of alcohol-dependence
Desire for alcoholpositive craving
Naltrexone, Nalmafen
Acute drinking
Dopamine release
Ondansetron5-HT3 antagonist
Chronic drinking
Topiramateantiepileptic
Withdravaldrug abstinence
Acamprosate
Disufiram
Relapse
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COCAINE ETHANOL I
cocaine plasma cc. ? (by 30)
ethanol ? vasodilatation ?absorption of cocaine
is better
first-pass liver metabolism?
ethanol plasma cc. ? (by 10)
cocaine ? vasoconstriction
? decreased absorption of ethanol ?
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COCAINE ETHANOL II
euphoria ?
paranoia, agitation ?
withdrawal dysphoria ?
cardiovascular effects ?
toxicity ?
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COCAINE ETHANOL III
coca-ethylene metabolite
its t1/2 is about double of cocaine it acts the
same way as cocaine
in animal experiments it is self-administrated