BASIC PHARMACOLOGY OF ALCOHOL (ETHANOL)

Ethanol is a small water-soluble that is absorbed rapidly from the gastrointestinal tract. After
ingestion of alchohol in the fasting state, peak blood alcohol concentrations concentrations are
reached within 30 minutes. The presence of food in the gut delays absorption by slowing gastric
emptying. Distribution is rapid, with tissues approximating the concentration in blood.The
volume of distribution for ethanol approximates total body water.(0.5-0.7 L/kg).For an
equivalent oral dose of alcohol, women have higher peak concentration than men, in part
because women have a total body content. In the central nervous system, the concentration of
ethanol rises quickly since the brain receives a large proportion of blood flow and ethanol
readily crosses biologic membranes.

Over 90% of alcohol consumed is oxidized in the liver; the rest is excreted through the lungs
and in the urine. The excretion of a small but consistent proportion of alchohol by the lungs is
exploited by breath alchohol tests that serve as a basis for a legal definition of “driving under
the influence” (80-100mg/dl for adults, 10mg/dl for < 21years) in many countries. At levels of
ethanol usually achieved in blood, the rate of oxidation follows zero-order kinetics,ie,it is
independent of time and concentration of the drug. The amount of alcohol oxidized per unit
time is approximately proportionate to body weight or liver weight, and rate of disappearance
of alcohol from the body is markedly reduced by liver damaged. The typical adult can
metabolize 7-10g (150-220 mmol) of alcohol per hour, the equivalent of approximately 10z of
beer, 3.5oz of wine, or 1 oz of distilled 80 proof spirits.

Two pathways of alcohol metabolism to acetaldehyde have been identified. Acetaldehyde is

then oxidized by a third metabolic process.

ALCOHOL Dehydrogenase Pathway: The main pathway for alcohol metabolism involves alcohol
dehydrogenase (ADH),a cytosolic enzyme that contains zinc and catalyzes the conversion of
alcohol to acetaldehyde.This enzyme is located mainly in the liver, but it can also be found in
other organs such as brain and stomach.

A significant amount of ethanol metabolism by gastric ADH occurs in the stomach in men, but a
smaller amount occurs in women, who appear to have lower levels of the gastric enzyme. This
difference in gastric metabolism of alcohol in women probably contributed to the sex related
differences in blood alcohol concentrations noted above. Both male and female alcoholics
exhibits lower gastric ADH activity than their nonalcoholic cohorts.

During conversion of ethanol to acetaldehyde, hydrogen ion is transferred from alcohol to the
cofactor nicotinamide adenine dinucleotide (NAD) to form NADH.As a net result, alcohol
oxidation generates an excess of reducing equivalents in the liver,chiefl as NADH.The excess
NADH production appears to underlie a number of metabolic disorder that are described
below.

NAD+ Ethanol NADP

CH Alcohol
MEOS
Dehydrogenase

NADH Acetaldehyde NADPH

4-Methylpyrazole

NAD+ Acetaldehyde
Dehydrogenase

NADH

Acetate Disulfiram

Figure 23-1.Metabolism of ethanol dehydrogenase and the microsomal ethanol-oxidizing

system(MEOS).Alcohol dehydrogenase and aldehyde dehydrogenase are inhibited by 4-
methylprazole and disulfiram,respectively.

B.MICROSOMAL ETHANOL OXIDISING SYSTEM(MEOS): This enzyme system also known as the
mixed function oxidase system uses NADP+ instead of NAD+ as a cofactor in the metabolism of
ethanol(Fi

At blood concentration below 100 mg/Dl (22 mmol/L), the MEOS system,which has a relatively
high K for alcohol,contributes little to the metabolism of ethanol.However,when large mounts
of ethanol are consumed,the alcohol dehydrogenase system becomes saturated owing to
depletion of the required cofactor,NAD+.As the concentration of ethanol increases above
100mg/dL, there is increased contribution from the MEOS system,which does not rely upon
NAD+ as a cofactor.

During chronic alcohol consumption,MEOS activity increases, thus induction of enzyme activity
is associated with an increase in various constituents of the smooth endoplasmic reticulum in
the liver. As a result, chronic alcohol consumption can result in significant increases not only in
ethanol metabolism but also in the clearance of other drugs that are eliminated by hepatic
microsomal enzyme systems. Similarly, other “inducing” drugs such as barbiturates may also
enhance the rate of blood alcohol clearance slightly. However,the effect of other drugs on
ethanol clearance is less important because the MEOS is not the primary pathway for ethanol
metabolism.

c.Acetaldehyde Metabolism: Much of the acetaldehyde formed from alchohol

appears to be oxidized in the liver, while several enzymes may be responsible for this reaction,
observations that acetaldehyde formed from alcohol appears to be oxidized in the liver. While
several enzyme systems may be responsible for this reaction, observations that acetaldehyde
concentrations in the liver after ethanol administration are only 100-350 µmol/L have led to the
conclusion that mitochondrial NAD+ dependent aldehyde oxidation. The product of this
reaction is acetate, which can be further metabolized to CO2 and water. Chronic alcohol
consumption results in a decreased rate of acetaldehyde oxidation in intact mitochondria.

Oxidation of acetaldehyde is inhibited by disulfiram,a drug used to deter drinking by alcohol-

dependent patients undergoing rehabilitation. When ethanol is consumed in the presence of
disulfiram, acetaldehyde accumulates and causes an unpleasant reaction of facial
flushing,nausea,dizziness and headache.

Some people, primarily of Asian descent, have a genetic deficiency in the activity in the activity
of the mitochondrial form of aldehyde dehydrogenase.When these individuals drink alcohol,
they develop high blood acetaldehyde concentrations and experience a flushing reaction similar
to that seen with the combination of disulfiram and ethanol.

PHARMACODYNAMICS OF ACUTE ETHANOL CONSUMPTION

A.CENTRAL NERVOUS SYSTEM: The central nervous system markedly affected by acute alcohol
consumption. Alcohol causes sedation and relief of anxiety and at higher concentrations,
slurred speech, ataxia, impaired judgment, and disoriented behavior condition usually called
intoxication or drunkenness. These central nervous system effects are moist marked as the
blood level is rising because acute tolerance to the effects of alcohol occurs after a few hours of
drinking. For example, a chronic alcoholic may appear sober or only slightly intoxicated with a
blood alcohol concentration of 300-400 mg/dl, whereas this level is associated with marked
intoxication or even coma in a nontolerant individual. The propensity of moderate doses of
alcohol to inhibit the attention and information processing skills as well as the motor skills
required for operation of motor vehicles has profound effects. Approximately half of all traffic
accidents resulting in a fatality in the united state involve at least one person with a blood
alcohol near or above the legal level of intoxication, and drunken driving is a leading cause of
death in young adults.
Like other sedative-hypnotic drugs, alcohol is a central nervous system depressant. At high
blood concentrations, it induces coma, respiratory depression, and death.

No specific receptor for ethanol has been identified. Instead, ethanol has been shown to affect
a large number of molecular processes, including neurotransmitter receptors for amines, amino
acids, and opioids; enzymes such as Na+/K+ ATPase, acetyl cholinesterase, adenylyl cyclase,
phosphoinositidespecific phospholipase C; the mitochondrial electron transport chain; and ion
channels such as those for Ca2+ . Much attention has focused on alcohol`s effects upon
neurotransmission by GABA and glutamate, the main excitatory and inhibitory
neurotransmitters in the central nervous system. Acute ethanol exposure enhances the action
of GABA at GABA-a receptors, which is consistent with the ability of GABA-mimetics to intensify
many of the acute effects of alcohol and of GABA-a antagonists to attenuate some of the
actions of ethanol. Ethanol also inhibits the ability of Glutamate to open the cation channel
associated with the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors. The NMDA
receptors is implicated in many aspects of cognitive functions, including learning and memory.

Alcohol has diverse effects at the cellular and tissue levels,particularly in the nervous system. In
trigeminal motoneurons, both intracellular and extracellular applications of ethanol depress
action potentials and excitatory and inhibitory postsynaptic potentials. In cerebellar purkinje
cells and in the dopamine containing neurons in the substantria nigra,pars compacta,and striate
nucleus, low concentrations of ethanol enhance the firing rate while higher doses inhabit it. In
other systems, including the lateral geniculate nucleus, the locus ceruleus, the mid brain raphe
nucleus and hippocampus neurons in culture. Only inhibitory effects have been observed. More
complex neuronal responses are similarly affected. For example, both the after discharge
following high frequency stimulation of hippocampal neurons and the frog spinal reflex are
enhanced by low doses of ethanol and inhibited doses(Lee et al,1986).

B.Heart: Significant depression of myocardial contractility has been observed in individuals who
acutely consume moderate amounts of alcohol,ie at biopsies in humans before and after
infusion of small changes that may be associated with impaired myocardial function.
Acetaldehyde is implicated as a cause of heart abnormalities by altering myocardial stores of
catecholamine.

C.Smooth muscles: Ethanol is a vasodilator, probably as a result of both central nervous system
effects(depression of the vasometer center) and direct smooth muscle relaxation caused by its
metabolite,acetaldehyde.In cases of severe overdose, hypothermia-caused by vasodilatation-
may be marked in cold environments. Ethanol also relaxes the uterus and before the
introduction of more effective and safer uterine relaxants (e.g. calcium blockers, magnesium
ion.NSAIDs, and β –adrenoceptor stimulants) was used intravenously for the suppression of
premature labor.
CLINICAL PHARMACOLOGY OF ETHANOL

Ethanol is one of the least potent drugs consumed by humans, yet it is the case of more
preventable morbidity and mortality than all other drugs combined with the exception of
tobacco. This is true even though moderate consumption of ethanol is associated with stress,
and even with a reduction in mortality .

The search for specific etiologic factors or the identification of significant

predisposing variables for alcohol abuse has generally led to disappointing results. Personality
type ,severe life stresses, psychiatric disorders, and parental role models are not reliable
predictors of alcohol abuse. Comparisons of differences in alcohol metabolism are unreliable,
and markers of disordered alcohol metabolism are unreliable ,and markers of disordered
alcohol metabolism are not sufficiently predictive. It is clear that alcohol abuse.Comparisons of
differences in alcohol abuse is not equally distributedin all social groups and abuse appears to
occurs at higher rate among relatives of alcoholics than in general population(Devor et al).The
rate of alcoholism in person with an alcoholic biologic parent is almost four times that of
selected control group-a.Finding that has now beenconfirmed by severalstudies.It is difficult to
ndistinguish between contributing factors of familial learnimng experiences and genetic
variables,but current evidence suggest that genetic factors play a role in defining human
alcoholic and medical complications.Genetic control of alcohol preference in animals has been
clearly established,and using using the abundance of new genetic markers for himans and
animals.an intensive search for genes that predisposed toward alcoholdependence is
undereay.What candidate is the capital letter A1 allele of the dopamine D2 receptor gene ,
which may be associated with a severe form of alcohol dependence. Since alcohol dependence
is a diverse disorder, at least several distinct genes are likely to be able to confer an increased
risk of developing alcohol dependence.

MANAGEMENT OF ACUTE ALCOHOL INTOXICATION

Nontolerant individuals who consume alcohol in large quantities develop typical effects of
acute sedative-hypnotic drug overdose along with the cardiovascular effects described above
(vasodilation, tachycardia) and gastrointestinal irritation. Since tolerance is absolute, even
chronic alcoholics may become severely intoxicated. The degree of intoxication depends upon
three factors: the blood ethanol concentration, the rapidity of the rise of the alcohol level, and
the time during which the blood level is maintained. The pattern of drinking, the state of the
absorptive surface of the gastriointestinal tract, and the presence in the body of other
medications also affect the apparent degree of intoxication.
 The most important goals in the treatment of acute alcohol intoxication are to prevent severe
respiratory depression and aspiration of vomitus. Even with very high blood ethanol levels,
survival is probable as long as the respiratory and cardiovascular systems can be supported. The
average blood alcohol concentration in fatal cases is above 400 mg/dL ;however,the lethal dose
of alcohol varies because of varying degrees of tolerance.

Metabolic alteration may require treatment of hypoglycemia and ketosis by administration

of glucose. Alcoholic patients who are dehydrated and vomiting should also receive electrolyte
solutions. If vomiting is severe,large amounts of potassium may be required as long as renal
function is normal. Especially important is recognition of decreased serum concentrations of
phosphate, which may be aggravated by glucose administration. Low phosphate stores may
contribute to poor wound healing, neurologic deficits, and an increased risk of infection.

MANAGEMENT OF ALCOHOL WITHDRAW SYNDROME

Abrupt alcohol withdrawal leads to a characteristic syndrome of motor agitation, anxiety,

insomnia, and reduction of seizure threshold. The severity of the syndrome is usually
proportionate to the degree and duration of alcohol abuse.However, this can be greatly
modified by the use of other sedatives as well as by associated factors (eg,diabetes,injury),In its
mildest form, the alcohol withdrawal syndrome of tremor, anxiety and insomnia occurs 6-8
hours after alcohol is stopped. These effects usually abate in 1-2 days. In some patients, more
severe withdrawal reactions occur in which visual hallucinations, total disorientation, and
marked abnormalities of vital signs occur.The more severe the withdrawal syndrome,the
graeter the need for meticulous investigation of possible underlying medical complications.The
mortality risks of severe alcohol. Withdrawal have been overstated in the past. The prognosis is
probably related chiefly to the underlying medical complications.

The major objective of drug therapy in the alcohol withdrawal period is prevention of
seizures, delirium, and arrhythmias. Potassium, magnesium, and phosphate balance should be
restored as rapidly as is consistent with renal function. Thiamine therapy is initiated in all cases.
Persons in mild alcohol withdrawal do not need any other pharmacologic assistance.

Specific drug treatment for detoxification in severe cases involves two basic principles:
substituting a long-acting sedative-hypnotic drug for alcohol and then gradually reducing
(“tapering”) the dose of the long-acting drug. Unfortunately, the most widely used “treatment”
for alcohol withdrawal is renewed alcohol intake. Although alcohol can be slowly tapered ,it is
psychological undesirable to maintain the patient on alcohol. Barbiturates such as
Phenobarbital have been used in the past for treatment of the alcohol withdrawal syndrome;
however, the benzodiazepines, with their wider margin of safety, are currently preferred for
this purpose. Since any benzodiazepine will prevent symptoms of alcohol withdrawal , the
choice of a specific agent in this class is generally based upon pharmacokinetic or economic
considerations.Long-acting benzodiazepines, including chlordiazepoxide, clorazepate and
diazepam,have the advantage of requiring less frequent dosing. Since their pharmacologically
active metabolites are eliminated slowely,, the long acting drugs provide a built in tapering
effect, while their disadvantage is that they with their active metabolites may accumulate over
time especially with patients with compromised liver function. Oxazepam is short acting, rapidly
metabolized and cleared , hence does not accumulate and used for patients with liver disease.

PHARMARCOTHERAPY OF ALCOHOLISM (READ UP)

1- Disulferam
2- Naltrexone