1 Jcelimpin ♥ Jmmission as of 1/11/12 The Alcohols J. ONA CRUZ, MD, MHPED, FPOGS The Alcohols (Ethanol, Methanol, Ethylene Glycol) - Very common abused substance Pharmacokinetics Pharmacodynamics Clinical Pharmacology Pharmacokinetics: Ethanol- Absorption and Distribution Small water soluble easily absorbed Rapid GIT absorption (esp. empty stomach) Food: Absorption retardant (slow gastric empting time) Rapid distribution- tissue levels approx. blood concentration (gender difference) - Alcohol is more readily distributed among females due to small body proportion - The smaller you are the more readily alcohol can be absorbed Levels rise fast in the brain (crosses biologic barriers) - The smaller the molecule, the more readily it can passed thru the BBB Pharmacokinetics: Ethanol- Metabolism and Excretion 90% liver oxidation, lungs, urine - Liver is responsible for most of the metabolism of alcohol - At higer doses, recruited by the lungs Zero order kinetics (150-220 mmHg/hour) - This causes accumulation of alcohol in our body Ethanol: Metabolic Pathways - Alcohol DH is the one the oxidizes ethanol into acetaldehyde normally - But with higher amounts of alcohol, the normal pathway is overwhelmed so the liver will activate the hepato-oxidizing system - In chronic alcoholism, the CYP450 takes its action which produces several effects - Once ethanol is converted into acetaldehyde, 2 nd enzyme will be activated which is the aldehyde DH which control the production of acetate that cause many adverse effects utilizing body processes and biosynthesis. Disulfiram inhibits the activity of aldehyde DH. - Acetaldehyde can be very toxic to body tissues that’s why it has to be broken down further and is also responsible for adverse reaction Alcohol Dehydrogenase Pathway The primary metabolic pathway Enzyme in the Liver, brain, stomach - Mostly concentrated in liver - A little in brain Reduced activity (some Asians) increased risk of alcoholism NADH accumulation* Gender differences (stomach ADH)
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1 Jcelimpin ♥ Jmmission as of 1/11/12
The Alcohols
J. ONA CRUZ, MD, MHPED, FPOGS
The Alcohols (Ethanol, Methanol, Ethylene Glycol)
- Very common abused substance
Pharmacokinetics
Pharmacodynamics
Clinical Pharmacology
Pharmacokinetics: Ethanol- Absorption and Distribution
- Alcohol is more readily distributed among females due to small body proportion
- The smaller you are the more readily alcohol can be absorbed
Levels rise fast in the brain (crosses biologic barriers)
- The smaller the molecule, the more readily it can passed thru the BBB
Pharmacokinetics: Ethanol- Metabolism and Excretion
90% liver oxidation, lungs, urine
- Liver is responsible for most of the metabolism of alcohol
- At higer doses, recruited by the lungs
Zero order kinetics (150-220 mmHg/hour)
- This causes accumulation of alcohol in our body
Ethanol: Metabolic Pathways
- Alcohol DH is the one the oxidizes ethanol into acetaldehyde normally
- But with higher amounts of alcohol, the normal pathway is overwhelmed so the liver will activate the hepato-oxidizing system
- In chronic alcoholism, the CYP450 takes its action which produces several effects
- Once ethanol is converted into acetaldehyde, 2nd enzyme will be activated which is the aldehyde DH which control the production of acetate that cause many adverse effects utilizing body processes and biosynthesis. Disulfiram inhibits the activity of aldehyde DH.
- Acetaldehyde can be very toxic to body tissues that’s why it has to be broken down further and is also responsible for adverse reaction
Alcohol Dehydrogenase Pathway
The primary metabolic pathway
Enzyme in the Liver, brain, stomach
- Mostly concentrated in liver
- A little in brain
Reduced activity (some Asians)
increased risk of alcoholism
NADH accumulation*
Gender differences (stomach ADH)
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- In men, ADH has more activity because they have more concentration in their stomach that’s why the ladies has more tendency to absorb the parent compound of alcohol
- Smaller distribution of women probably explain why women has to be symptomatic in terms of alcohol
- In men, they are able to metabolized alcohol in their stomach due to presence of ADH
In some Asian populations, there are those with ADH that have reduced activityincreased risk of alcoholism
- Due to gender and genetic make up
NADH metabolic abnormalities in chronic alcoholism-
For example, elevated levels of NADH cause the formation of abnormally high levels of lactic acid, which in turn reduce the capacity of the kidney to excrete uric acid.
Excessive uric acid in the body can exacerbate gout, a disorder characterized by extremely painful swelling of certain joints.
Therefore, alcohol-induced increases in NADH levels and, subsequently, uric acid levels, which can be worsened by other alcohol-induced metabolic effects, may at least partly explain the common clinical observation that excessive alcohol consumption causes or aggravates attacks of gout.
In addition, increased NADH promotes the generation of the building blocks of fat molecules and reduces the breakdown of fats in the liver, thereby contributing to fat accumulation in that organ.
Microsomal Ethanol Oxidizing System (MEOS)
Activated when alcohol levels are high (ADH system saturation >100mg/dl)
Involves CYP P450s
Activated in chronic alcoholism*
faster metabolism of other drugs
generation of more toxic metabolites
Chronic alcoholism-MEOS is activated so many other drugs have faster clearanceincrease toxic products of metabolism(toxins, free radicals, hydrogen peroxide)
Acetaldehyde Metabolism by Acetaldehyde Dehydrogenase
Mitochondrial NAD-dependent ALDH
Oxidation is inhibited by disulfiram *è acetaldehyde elevation (untoward reactions):
protective against alcoholism?
greater risk of liver disease
- Disulfiram is a drug to address addiction and to induce the relapse state but the problem is that it is able to inhibit very well the aldehyde DH
* exhibited by other drugs
* Asians-lower activity of ALDH
- Alcohol can reduce the clinical efficacy of other drugs taken
- Ex. An antibiotic that is metabolized by CYP450, it clinical effect would be reduced because it was metabolized earlier
- Due to action of CYP450, metabolites produced rapidly can be toxic to liver especially during continuous utilization of alcohol
- Asian has lower concentration of ADH compare to Caucasian and Africans
- If acetaldehyde is increased, it can produce untoward reactions such as generalized pain, flushing, nausea and vomiting as well as autonomics fluctuation
- Metronidazole not taken with alcohol
Accumulation of acetaldehyde flushi, has disulfiram reactionng, nausea, vomiting, dizziness, headache
Other drugs with disulfiram effect when taken with alcohol: metronidazole, cefotetan, trimethoprim
Some Asians have lower ALDH activity reduced likelihood of alcoholism due to earlier appearance of untoward reactions from accumulation of acetaldehyde but this increases risk of severe liver disease
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Pharmacodynamics: CNS
- The no.1 effect of alcohol is neural: to the nervous tissue
- It affects more areas of the brain
- Starts with sedation
Sedative
Anxiolytic
Slurred speech
Ataxia
Impaired judgement – which can lead to accident especially when driving
Disinihibited behavior
Impairment of attention and information processing – cognitive performance are also affected
Impairment of motor skills
CNS depression, coma, death
- Alcohol can also lead to death especially in women
- Remember! Alcohol is a sedative as well as depressant it can alter the function of the brainstem and also the autonomic function
(Tolerance in Chronic Alcoholics)
- Asian has lower threshold for respiratory depression
- Chronic alcoholics can develop tolerance. But at some point tolerance STOP and the individual may
experience this clinical effect. So chronic alcoholics are not exempted to the damage, they also experience cellular damage due to exposure to higher level of alcohol
- Resistance and tolerance was only up to some extent. Once tolerance stop, manifestation can be seen
Ethanol and Neurotransmission
Glutamate and the NMDA receptor
GABA – mostly affected arising to depressant effect
- Has the dominant effect
Ethanol affects large number of proteins trhat are involved insignalling e.g. nts receptors for amines, amino acids, opioids; enzymes such as Na/K ATPase, adenyl cyclase, phospholipase C, ion channels
Acute alcohol exposure enhances GABA (main inhibitory nts in the CNS) and inhibits glutamate in opening NMDA glutamate receptors (main excitatory nts in the CNS)
Pharmacodynamics: Heart
Depression of myocardial contractility – that’s why it is not possible to see alcoholics who has a congestive heart failure
Pharmacodynamics: Smooth Muscles
Vasodilators (central and direct effects):
Hypothermia esp. in cold environments (severe overdoses)
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- Commonly mistaken by layman’s that taking alcohol may increase temperature but in fact it does not
Uterine relaxant – not use for practical value
Chronic Alcohol Consumption: Effects and Consequences
Risk of severe disease greater with preexisting hepatitis B or C
PATHOGENESIS OF ALCOHOLIC LIVER DISEASE-
MULTIFACTORIAL:
1. Metabolic effects of ethanol oxidation in the liver
2. Dysregulation of fatty acid oxidation and synthesis
3. Activation of innate immune system
e.g. TNF - α
*By direct effects of ethanol or its metabolites or by bacterial endotoxins gaining access from the GIT due to alcohol induced changes in the intestinal mucosa
- mucosa lining are destroyed and become corrosive leading to malnutrition and eventually malabsorption of folic acid
- Spectrum of Fatty liver alcoholic hepatitis liver cirrhosis
- In ethanol toxicity, the individual phagocytes become less efficient in function and was not able to convert glycogen ↑ glycogen will be deposited in the liver causing the liver to enlarged (fatty liver)
- Activation of cytokine and TNF- alpha causing liver cirrhosis
- Asian women has less defenses against alcoholism due to gender and genetic make up
*severity depends on dose, rate and duration of consumption
Psychological dependence (cravings)
- Urge or compulsion to take substances
- Recalcitrant disease keep on coming back
Molecular basis of tolerance and dependence
LARGELY UNCLEAR
Tolerance: ethanol upregulation of a pathway
Dependence: overactivity of same pathway after dissipation of ethanol effects
Changes in GABA neurotransmission – according to most studies
Changes in levels of neurotransmitters involved in brain reward circuits (e.g. serotonin, opioids, dopamine)
- Nowadays! They try to develop drug to address addiction but no successful drug was produced
Nervous System
Neurotoxicity
generalized symmetric peripheral nerve injury (distal paresthesias of hands and feet)
gait disturbances and ataxia – motor and gait
abnormality
dementia
demyelinating disease
impairment of visual acuity and optic nerve degeneration
Wernicke-Korsakoff syndrome – thiamine deficiency
Cardiovascular System
Cardiomyopathy and heart failure
Arrhythmias
Hypertension
Coronary Heart Disease
#1 dilated cardiomyopathy, ventricular hypertrophy, fibrosis. Alcohol induced changes in heart cells- membrane disruption, depressed function of mitochondria and sarcoplastic reticulum, intracellular accumulation of phospholipids and fatty acids, upregulation of voltage dependent calcium channels
#2 atrial and ventricular arr., reflects abnormalities of potassium and magnesium metabolism and enhanced release of catecholamines
#3 independent of obesity, salt intake, coffee intake, cigarette smoking
#4 cardioprotective effects of moderate drinking is still unestablished-based on ROH ability to raise HDL
Blood
Mild anemia (folic acid deficiency)
IDA from gastrointestinal bleeding
Hemolytic syndrome
- G6PD and thalassemia bad reaction to alcohol
Endocrine System and Electrolyte Balance
Gynecomastia, testicular atrophy
- Alcohol is toxic to testis
- Induces testicular atrophy testosterone production decreases
- Unopposed action of estrogen
Fluid and electrolyte imbalances (ascites, edema, effusions)
Potassium depletion
Hypoglycemia
Ketosis – due to damage kidney
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Fetal Alcohol Syndrome
FAS
- Cause cognitive impairment
- “fetal alcohol effect”
- Pregnant, “NO TO ALCOHOL” even a small amount. there is no threshold for alcohol. Since alcohol is a small molecule it can cross the placenta and produce untoward effects to the fetus
IUGR
Microcephaly
Poor coordination
Underdeveloped midfacial area (flat face)
Minor joint anomalies
Congenital heart anomalies
Mental retardation
FAS Mechanism
Immune System
- Immunodepressant chronic alcoholics prone to pneumonia
Immune function in some areas (lung) are inhibited while hyperactivity is triggered in other tissues (liver, pancreas)
Chronic use leads to inflammatory damages in liver and pancreas, increased susceptibility to lung infections
Increased cancer risk
- Carcinogenic because of toxic metabolites prone to asian due to ↑ acetaldehyde concentration especially female
Mouth, pharynx, larnyx, esophagus, liver, breast
Threshold of consumption for carcinogenic effects?
Metabolites e.g. acetaldehyde
Changes in folate metabolism
Effects of chronic inflammation
Alcohol and Drug Interactions: P’kinetic
- Alcohol (+) CYP450 enhance the clinical effect
- Always additive and synergistic effect with other drugs sedative hypnotics
Alcohol induced changes in drug-metabolizing enzymes: MOST common (chronic alcohol use)
ex. Acetaminophen and chronic use of alcohol
Alcohol may also inhibit metabolism of other drugs (acute alcohol intake)
ex. Phenothiazines, TCAs, sedative hypnotics
Chronic alcohol: This enhances metabolic biotransformation of other drugs. Ethanol-mediated induction of hepatic CYP 450 especially with regards acetaminophen.Chronic alcohol use (3 or more drinks daily) increases risk of hepatotoxicity due to toxic or high toxic levels of acetaminophen converted to hepatotoxic active metabolites
Acute alcohol: may induce decreased enzyme activity or liver blood flow
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Alcohol and Drug Interactions: P’dynamics
Additive CNS depression with sedative-hypnotics, other depressants
Potentiation of effects of vasodilators and oral hypoglycemics
Clinical Pharmacology ETHANOL
Acute Intoxication: Management
Goal: Prevention of severe respiratory depression and aspiration
Average fatal blood levels (>400mg/dL)- maybe variable due to differences in tolerance
Address hypoglycemia and ketosis: Glucose
Wernicke-Korsakoff syndrome: Thiamine
Vomiting and dehydration: Fluid and electrolyte replacement
Alcohol Withdrawal Syndrome: management
Goal: prevention of seizures, delirium, arrhythmias
- Seizure: common manifestation of withdrawal syndrome
Prompt resoration of potassium, magnesium and phosphate balance
Thiamine
Mild cases need no other pharmacologic assistance
- Gradually taper the substances to protect the patient from withdrawal syndrome (esp. opiods)
AWS: motor agitation, anxiety, insomnia, reduction of seizure threshold, visual hallucinations, total disorientation, marked abnormalities of vital signs
Severity is proportional to degree and duration of alcohol abuse
Alcohol Detoxification: Basic Principles
Substitution with long-acting sedative hypnotic then gradual tapering of dose of the drug (benzodiazepines esp. long-acting ones)* thru for chronic alcoholics
- Dosage interval should be far apart
- Abrupt drop lead to withdrawal syndrome
- Opioid withdrawal “worst effect!”
Oral in mild to moderate; parenteral for severe cases
Tapering of sedative- hypnotics takes place over several weeks
*chlordiazepoxide, ,chlorazepate, diazepam-less frequent dosaging- these long acting agents have pharmacologically active metabolites that are eliminated slowly: Built-in tapering effect.
However, these agents and their metabolites tend to accumulate esp in liver disease. Short acting agents (e.g. lorazepam, oxazepam) are rapidly converted to inactive metabolites that are water soluble and do not accumulate. Hence, these are preferred for alcoholic patients with liver disease.
Alcoholism: Treatment
Primary treatment after detoxification: intensive psychosocial therapy
Treatment of associated disorders such as depression or anxiety with drugs and counseling
People who continue to drink ROH despite medical or societal consequences related to consumption suffer from alcoholism. It is a complex disorder with genetic and environmental determinants
Drugs for adjunctive treatment: NALTREXONE
- moderate reduction in relapse state
opioid receptor antagonist (p.o.50 mg /day) at the μ(link between alcohol consumption and opioids)
long acting agent that reduces craving and rate of relapse
caution for alcoholics with hepatic enzyme elevation; not given with disulfiram (hepatotoxic)
not given for alcoholics who are also dependent on opioids
Drugs for adjunctive treatment: ACAMPROSATE
Weak NMDA-receptor antagonist and GABA A receptor activator*
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Reduces short-term and long term (>6 mos) relapse rates when used with psychotherapy