pharmacodynamics of ethanol, alcohol abue signs and symptoms and their treatment

1. ALCOHOL DYNAMICS AND ABUSE
BY
DR. SYED SALEEM AHMED
PROFESSOR OF PHARMACOLOGY AND
CLINICAL THERAPEUTICS

10. ALCOHOL ABUSE AND DEPENDENCE
• A primary chronic disease with genetic psychosocial
and environmental factors: (1) Often progressive and
fatal & characterized by impaired control over drinking
(2)Preoccupation with the alcohol (3) Use of alcohol
despite future consequences and (4)Distortions of
thinking most notably denial.
• Population-based epidemiologic studies have shown
that alcohol use disorders are among the most
prevalent medical behavioral or psychiatric disorders
in the general population.
• The prevalence in alcohol abuse and dependence in
general outpatient and inpatient medical settings has
been estimated between 15 and 40%.

11. PHARMAOKINETICS AND ALCOHOLISM
• Women have lower levels of gastric alcohol
dehydrogenase (enzyme responsible for metabolizing
alcohol), they experience higher blood alcohol
concentrations than men.
• The absorption of alcohol can be affected by other
factors, including the presence of food in the stomach
and the rate of alcohol consumption.
• By means of metabolism in the liver, alcohol is
converted to acetaldehyde and acetate .
• Metabolism is proportional to body weight
• A genetic variation in a significant proportion of the
Asian population alters the structure of an aldehyde
hydrogenase isoenzyme, resulting in aldehyde syndrome

12. ALCOHOL WITHDRAWAL
• The clinical manifestations of alcohol withdrawal
include hyperactivity resulting in tachycardia and
diaphoresis.
• Patients also experience tremulousness, anxiety, and
insomnia. More severe alcohol withdrawal can result in
nausea and vomiting, which can exacerbate metabolic
disturbances.
• Perceptual abnormalities, including visual and auditory
hallucinations and psychomotor agitation, are common
manifestations of more moderate-to-severe alcohol
withdrawal.
• Grand mal seizures commonly occur during alcohol
withdrawal, although they do not generally require
treatment beyond the acute withdrawal phase.

13. ALCHOL WITHDRAWAL SYDROME
• Tremor is typically among the earliest symptoms and can occur
witahin 8 hours of the last drink. Symptoms of tremulousness
and motor hyperactivity peak within 24 to 48 hours. Although
mild tremor involves the hands, more severe tremors can
involve the entire body and greatly impair a variety of basic
motor functions.
• Perceptual abnormalities begin within 24 to 36 hours after the
last drink and resolve within a few days.
• The withdrawal seizures are generalized tonic-clonic and most
often occur within 12 to 24 hours after reduction of alcohol
intake.
•The most severe manifestations of the alcohol withdrawal
syndrome are delirium tremens. This symptom complex
includes
disorientation, confusion, hallucination, diaphoresis, fever, and
tachycardia. Delirium tremens begin after 2 to 4 days of
abstinence, and the most severe form can result in death.

14. MAIFESTATION OF ALCOHOLISM
• Acute manifestations, including intoxication and withdrawal,
are generally stereotypical in their appearance and time course,
• Chronic manifestations tend to be more varied.
Many patients with alcohol dependence may be without
evidence of any chronic medical manifestations for many years.
• As time goes on, however, the likelihood that one or more of
these manifestations will occur increases considerably.
• The primary organ systems involved include the nervous
system, cardiovascular system, liver, gastrointestinal system,
pancreas, hematopoietic system, and endocrine system.
• Patients may have the risk of a variety of malignancies, such as
head and neck, esophageal, and liver cancers.
• Excessive alcohol use often causes significant psychiatric and
social morbidity.

15. ADVERSE EFFECTS OF ALCOHOL
(1) In the CNS, the major effect is cognitive impairment.
Patients may present with mild-to-moderate short-term or long-
term memory problems or may have severe dementia
resembling Alzheimer’s disease .
• The deficiency of vitamins such as thiamine may have a major
impact in terms of promoting alcoholic dementia and severe
cognitive dysfunction, as is seen in Korsakoff’s syndrome.
• Alcohol also causes a polyneuropathy that can present with
paresthesias, numbness, weakness, and chronic pain.
• As with the CNS, peripheral nervous system effects are thought
to be caused by a combination of the direct toxicity of alcohol
and nutritional deficiencies.
• A small proportion (<1%) of patients with alcohol dependence
may develop midline cerebellar degeneration, which presents as
an unsteady gait.

16. (2) CARDIOVASCULAR SYSTEM
• The most common cardiovascular complications of chronic
alcohol consumption are cardiomyopathy, hypertension, and
supraventricular arrhythmias.
• Alcoholic cardiomyopathy can present clinically in a manner
similar to other causes of heart failure. It is the most common
cause of non-ischemic cardiomyopathy in Western countries (44%).
• Alcoholic cardiomyopathy also responds to conventional
treatments for heart failure. Abstinence from alcohol can result in
significant improvement.
• Increasing levels of alcohol consumption also are associated with
systolic and diastolic hypertension .
• The most common arrhythmias associated with chronic alcohol
use include atrial fibrillation and supraventricular tachycardia with
acute intoxication and withdrawal.
• Alcoholic cardiomyopathy also is associated with arrhythmias, in
particular, ventricular arrhythmias.

17. (3) LIVER
• Alcohol abuse is the major cause of morbidity and mortality
from liver disease.
• Factors that predispose to early liver disease include the
quantity and duration of alcohol exposure, female gender, and
malnutrition.
• The clinical manifestations includes acute fatty liver, alcoholic
hepatitis, and cirrhosis.
• Fatty liver can be asymptomatic or associated with nonspecific
abdominal discomfort ad generally improves with abstinence
from alcohol.
Alcoholic hepatitis can present as an asymptomatic condition
identified through abnormalities in liver enzymes or as an acute
episode with abdominal pain, nausea, vomiting, and fever.
• Patients with alcoholic hepatitis have high levels of aspartate
aminotransferase in the blood and elevated levels of γ-
glutamyltransferase. The hepatitis improves with abstinence
from alcohol.

18. (4) HEPATIC CIRRHOSIS
• It is a major cause of death in the United States.
• Although patients are often asymptomatic, patients
with more advanced cirrhosis may present with a variety
of symptoms and signs, including jaundice, ascites, and
coagulopathy.
• Cirrhosis is also associated with gastrointestinal
bleeding from esophageal varices.
• Although there is some controversy about the use of
liver transplantation to treat patients with alcoholic
cirrhosis, physicians believe that patients in established
recovery are good candidates for liver transplantation in
case of advanced cirrhosis.

19. (5) GASTROINTESTINAL DISEASE.
• Chronic alcohol use is associated with a variety of esophageal
problems, including esophageal varices, Mallory-Weiss tears, and
squamous cell carcinoma of the esophagus.
• The risk of squamous cell carcinoma is increased further in
patients who smoke tobacco and drink alcohol.
• Acute alcoholic gastritis presents with abdominal
discomfort, nausea, and vomiting.
(6) PANCREAS
• The risk of pancreatitis in individuals with alcohol dependence is
approximately four times that in the general population.
• It may present with severe abdominal
pain, nausea, vomiting, fever, and hypotension and can be life-
threatening.
• Individuals with recurrent acute pancreatitis may develop
chronic pancreatitis, which presents with chronic abdominal
pain, malabsorption, weight loss, and malnutrition.

20. (7)HEMATOPOIETIC SYSTEM
• The anemia can be multifactorial (e.g., blood loss, nutrient
deficiency, secondary to liver disease and hyper-splenism).
• The prevalence of anemia ranges from approximately 10 to 60%.
Gastrointestinal blood loss owing to Mallory-Weiss tears , alcoholic
gastritis or bleedig esophageal varices.
• Dietary folate deficiency causes megaloblastic anemias .
• Alcohol also has a direct toxic effect on the bone marrow, which can
lead to sideroblastic anemia that resolves after abstinence .
• Alcohol can suppress megakaryocyte production and causes
thrombocytopenia manifesting as petechiae or bleeding .The platelet
counts usually returning to normal after cessation of alcohol intake.
• Alcohol-related immune dysfunction, as evidenced by decreased
production and function of white blood cells and derangement in
humoral and cell-mediated immunity causes higher risk for infectious
diseases, such as pneumonia and tuberculosis.
• The hypersplenism with cirrhosis contributes to the increased risk of

21. (8) MALIGNANCIES.
• Alcohol intake has been associated with upper
digestive, respiratory, and liver malignancies.
• Alcohol use is associated with squamous cell carcinomas of the
esophagus and of the head and neck.
• Either heavy alcohol use or smoking individually increases the
rate of oropharyngeal cancer by about 6 to 7 times that of the
general population, whereas the risk for people with both risk
factors is about 40 times.
• Patients with alcohol-induced liver disease with a history of
hepatitis B/C are at increased risk for hepatocellular carcinoma
• Chronic alcohol use also associated with malignancies of the
breast , prostate , pancreas, cervix, lung and colon. Hormonal
mechanisms and direct carcinogenic effects of alcohol have been
postulated as causes of this association.
• The cervical cancer with alcohol dependence may be due to
alcohol-associated with high-risk sexual behaviors .

23. (9)OTHER MEDICAL ISSUES.
• Gout has been associated with alcohol abuse, and flares can occur
at lower serum urate levels than in nonalcoholic patients .
• Alcoholic ketoacidosis which usually follows an alcoholic binge,
presents as nausea, vomiting, abdominal pain, volume depletion.
• Mild or nonspecific
• Abnormalities in thyroid function, may reflect abnormalities in the
clearance of TSH oor elevated circulating estrogens .
• Infertility and menstrual irregularities may occur presumably
owing to alcoholic induced disruption in hypothalamic-pituitary
dysfunction, gonadal toxicity, and impaired hepatic metabolism of
circulating hormones.
• Hypogonadism is highly prevalent in male alcoholics with cirrhosis
• Alcohol dependence also is associated with dental and
periodontal disease
• Variety of dermatologic problems, including spider angiomas and,
• Patients with poor hygiene and skin infestations.

24. (11) PSYCHIATRIC ISSUES
• The prevalence of anxiety disorders is about 40%, and
of affective disorders is about 30%.
• Antisocial personality disorder is also more common.
These psychiatric problems are more prevalent during
periods of heavy drinking and withdrawal.
• All patients with alcohol use disorders require careful
screening for psychiatric illnesses. Effective treatment of
underlying psychiatric disorders may result in improved
drinking behaviors.
(12) OTHER BEHAVIORAL AND PSYCHOSOCIAL ISSUES
• There may domestic injuries, trauma, motor vehicle
accidents, and burns . Tobacco and other drug abuse are
more prevalent in people with alcohol problems than in
the general population.

25. Both acute and chronic alcohol use can lead to
impotence in men. Increased blood alcohol
concentrations lead to decreased sexual
arousal, increased ejaculatory latency, and
decreased orgasmic pleasure

26. USE OF STANDARDIZED SCREENING INSTRUMENTS
• Many standardized questionnaires have been developed to
detect alcohol abuse and dependence.
• The two questionnaires that have been evaluated most
extensively in medical settings are the CAGE (Cut
down, Annoyed, Guilty, and Eye opener) questionnaire and the
Alcohol Use Disorder Identification Test (AUDIT).
• The CAGE questionnaire includes four questions and is scored
by giving 1 point for each positive response. Given that the
word ever is used in each CAGE question, by definition this
instrument is designed to detect lifetime alcohol problems and
does not distinguish between lifetime problems and current
problems.
• To screen for alcohol abuse and dependence, the CAGE has a
sensitivity of 43 to 94% and a specificity of 70 to 97% when a
cutoff score of 2 is used to indicate a “positive” result.

29. BENZODIAZEPINES IN ALCOHOL WITHDRAWAL
(1) The specific benzodiazepine and dose often depend
on:
(i) Severity of withdrawal:
(higher doses used if more severe)
(ii) Presence of liver disease
(Patients with severe liver disease should receive lower
doses or shorter acting medications be used)
(iii)Response to prior doses of medication.
*The amount of medication per dosing period is
decreased gradually as the withdrawal syndrome abates.
*Individualized “symptom-triggered” dosing approach:
Benzodiazepines are administered on a dose-by-dose basis
(e.g., 25 to 100 mg of chlordiazepoxide hourly) as guided
by withdrawal symptoms

30. BENZODIAZEPINES AND OTHER DRUGS
(1)Long-acting benzodiazepines: chlordiazepoxide,
clorazepate, and diazepam, have the advantage of
requiring less frequent dosing.
(2) Short-acting benzodiazepines: lorazepam and
oxazepam are rapidly converted to inactive water-
soluble metabolites that will not accumulate, thus not
•
causing adverse effect on liver. So short-acting drugs
are useful in alcoholic patients with liver disease.
OTHER DRUGS
β-Blockers (atenolol and propranolol), α-agonists
(clonidine), and antiepileptics (carbamazepine)
improve signs and symptoms of alcohol withdrawal.

31. PREVENTION OF RELAPSE
Three commonly used psychotherapeutic techniques:
(1) Motivational enhancement therapy:
The patients identify reasons for staying away
from alcohol.
(2) The 12-step facilitation therapy:
The patients use the principles to help focus their
attention on abstinence.
(3) Cognitive behavioral coping skills therapy:
The patient identifies factors which trigger to
alcohol use and to help deal with the triggers when
they are present.

32. PHARMACOTHERAPY TO PREVENT RELAPSE TO
ALCOHOL USE
• The drugs disulfiram, naltrexone and acamprosate are useful
for the treatment of alcohol dependence prevention.
(1) DISULFIRAM:
• It is designed to prevent alcohol use by causing a severe
adverse reaction when patients use alcohol. The disulfiram
reaction (aldehyde syndrome) which includes flushing, nausea,
vomiting, diarrhea and hypotension mediated by the inhibition
of alcohol dehydrogenase resulting increase in blood levels of
acetaldehyde and acetate after ingestion of alcohol.
• Disulfiram is effective in reducing alcohol intake in highly
motivated patients.

33. (2) NALTREXONE.
• Naltrexone decreases alcohol use by diminishing the euphorigenic
effects of alcohol and by decreasing craving in alcohol-dependent
patients.
• Alcohol-dependent patients who receive naltrexone (50 mg/day)
are more likely to remain abstinent and the effects persist after
discontinuation of treatment.
• Side effects of naltrexone may be self-limited nausea in about
10% of patients. Dose-related hepatotoxicity seen with high-dose
naltrexone (300 mg/day).
• Mild liver enzyme abnormalities are not a contraindication but
patients should be followed with repeat liver enzymes.
• Patients with acute hepatitis or liver failure should not be given
naltrexone

34. (3) ACAMPROSATE (N-ACETYLHOMOTAURINE )
• It reduces the incidence of relapse and prolongs
abstinence.
• It decreases drinking frequency and reduces relapse
drinking in abstinent alcoholics.
• It acts in a dose-dependent manner (1.3 to 2 g/day} and
appears to have efficacy similar to that of naltrexone.
• Acamprosate generally is well tolerated by patients,
with diarrhea being the main side effect.
• Concomitant use of disulfiram increases effectiveness of
acamprosate, without adverse drug interaction
• The mechanism of action of acamprosate is obscure. It
modulates CNS neurotramitters.
• It causes competitive inhibition of NMDA receptors) and
affects the inhibitory GABA system.

35. MAJOR PATHWAYS OF ETHANOL METABOLISM
A

36. •

37. Other Pharmacologic Treatments to Prevent Relapse
• Other medications that have shown promise include
ondansetron,6 bromocriptine, and sodium valproate.
• Other drugs have shown possible benefits in patients
with concurrent depression (e.g., fluoxetine) or anxiety
(e.g., buspirone) or no effect (e.g., lithium).

38. • Many female alcoholics complain of decreased
libido, decreased vaginal lubrication, and menstrual cycle
abnormalities.
• An increased reaction time, diminished fine motor
control, impulsivity, and impaired judgment become evident
when the concentration of ethanol in the blood is 20 to 30
mg/dl. More than 50% of persons are grossly intoxicated by a
concentration of 150 mg/dl. In fatal cases, the average
concentration is about 400 mg/dl.

39. ION CHANNELS AND ALCOHOL
A number of ion channels in the CNS are sensitive
to ethanol, including representatives of the ligand-gated
and G protein-coupled receptor families and voltage-
gated ion channels. Substantial
biochemical, electrophysiological, and behavioral data
implicate the GABAA receptor as an important target for
the in vivo actions of ethanol.
Bicuculline, a GABAA-receptor antagonist, and
antagonists at the benzodiazepine-binding site on
GABAA receptors decrease alcohol consumption in
animal models.
The administration of the GABAA-receptor agonist
muscimol into specific regions of the limbic system in
rats can substitute for ethanol in discrimination studies.

40. • Neuronal nicotinic acetylcholine receptors also may
be prominent molecular targets of alcohol.
Both enhancement and inhibition of nicotinic
acetylcholine receptor function have been reported
depending on the concentrations of ethanol tested.
There is an association between nicotine exposure
(smoking) and alcohol consumption in human beings.
Tolerance is defined as a reduced behavioral or physiological
response to the same dose of ethanol
• There is an increase in NMDA-receptor function after
chronic alcohol ingestion that may contribute to the
CNS hyperexcitability and neurotoxicity seen during
ethanol withdrawal.

41. • Physical dependence is demonstrated by the elicitation of a
withdrawal syndrome when alcohol consumption is terminated.
• The symptoms and severity are determined by the amount and
duration of alcohol consumption and include sleep disruption,
autonomic nervous system (sympathetic) activation, tremors, and
in severe cases, seizures.
• In addition, two or more days after withdrawal, some individuals
experience delirium tremens, characterized by hallucinations,
delirium, fever, and tachycardia. Delirium tremens can be fatal.
• Another aspect of dependence is craving and drug-seeking
behavior, often termed psychological dependence.

42. • Alcoholism "runs in families“: shows that alcohol dependence
has a genetic component.
• It generally is in the range of 40% to 60%, which means that
environmental variables also are critical for individual
susceptibility to alcoholism.
• This has been attributed to genetic differences in alcohol- and
aldehyde-metabolizing enzymes.
• Specifically, genetic variants of ADH that exhibit high activity
and variants of ALDH that exhibit low activity protect against
heavy drinking. This is so because alcohol consumption by
individuals who have these variants results in accumulation of
acetaldehyde, which produces a variety of unpleasant effects.
• The genes for susceptibility to alcoholism identified in genome
in humans include the dopamine D4 receptor, the 1 subunit of
the GABAA receptor, and tyrosine hydroxylase, an enzyme
involved in the synthesis of dopamine, norepinephrine, and
epinephrine

43. MISCELLANEOUSW DRUGS
• Ondansetron, a 5-HT3-receptor antagonist and antiemetic drug
reduces alcohol consumption in laboratory animals .
• Ondansetron is effective in the treatment of early-onset
alcoholics, who respond poorly to psychosocial treatment alone.
• Ondansetron administration lowers the amount of alcohol
consumed, particularly by drinkers who consume fewer than 10
drinks per day. No effect on the pharmacokinetics of ethanol.
*Topiramate, a drug used for treating seizure disorders appears
useful for treating alcohol dependence.
• Compared with the placebo group, patients taking topiramate
achieved more abstinent days and a lower craving for alcohol .
• The mechanism of action of topiramate is not well understood
but is distinct from that of other drugs used for the treatment of
dependence (e.g., opioid antagonists), suggesting that it may
provide a new and unique approach to pharmacotherapy of
alcoholism.

44. The volume of
distribution for ethanol approximates total
body water (0.5–0.7 L/kg).
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 abnormalities that have been characterized as fetal alcohol syndrome
include (1) intrauterine growth retardation (2) micro-cephaly, (3) poor
coordination, (4) underdevelopment of midfacial region appearing as a flattened
face, and (5) minor joint anomalies.
• More severe cases may include congenital heart defects and mental retardation.

45. Other clinical trials are focusing on:
(1) 5-HT system:
(i) Selective serotonin reuptake inhibitors (SSRI)
such as fluoxetine as well as
(ii) Selective serotonin receptor ligands such as
buspirone, a 5-HT1A receptor partial agonist; and
(iii) 5-HT2 receptor antagonist e.g. ritanserin.
(2) DA receptor antagonists e.g. selective antagonists
of D1 and D2 dopamine receptors being studied
(3) Drugs acting through GABA and glutamate systems
are also under investigation.
(4) The NMDA receptor is implicated in cognitive
function, including learning and memory. Blackouts
"periods of memory loss - with high levels of alcohol -
may be due to inhibition of NMDA receptor activation.