King Saud University College of Medicine 2nd Year, 1st Block

CNSCNS BlockBlock Ethyl ()

Pharmacokinetics Genetic variation Mechanism of alcohol of action of metabolism alcohol withdrawal Alcohol symptoms Metabolism Alcohol Management excretion of alcoholism withdrawal Hepatic The influence of Cellular alcohol Processing of alcohol

Chronic Acute Acute alcohol use actions of Alcohol and alcohol (Alcoholism) alcohol drug interactions In mild- In severe Chronic alcohol moderate amounts amounts Ethyl alcohol (ethanol): Ethyl alcohol (ethanol) is the most commonly abused drug in the world.

Pharmacokinetics Metabolism in gastric mucosa &

 lipophilic . Oxidation of ethanol

 It crosses all biological Aldehyde dehydrogenase *cyt-p450 (CYP2E1)* +* membranes & completely acetate + reduces NAD to NADH. absorbed from GIT. “Crosses placenta and Acetate CO2 + water. excreted in milk “* 1- Oxidation is : remove H so, the name of for oxidation is dehydrogenase  distributed to all body 2- Oxidation done by 2 type of : 1-Non-microsomal enzyme (in mitochondria and tissues cytosol) 2- hepatic microsomal enzyme mainly cyt-p450 (CYP2E1) in liver. “Volume of distribution = 3- we need co-enzyme which is NAD to take the H that dehydrogenase remove it. Total body water “ *It causes Irreversible fetal  Low ethanol conc., > minor metabolism by MEOS (microsomal ethanol- alcohol syndrome: oxidizing system) CYP450 “CYP2E1” Intrauterine growth retardation (due to hypoxia) -Congenital malformation  Continuous alcohol use > enzyme is stimulated > alcohol metabolism & (Teratogenesis): tolerance*.

-Microcephaly -Impaired facial development -Congenital heart defect N.B\ (Acetaldehyde) more toxic than alcohol -Physical & mental retardation. Pharmacokinetics Alcohol excretion:

Acute *alcohol Chronic alcohol . Excreted unchanged in urine (2-8%). consumption consumption inhibits CYP450 2E1 so decrease induces liver microsomal enzyme . Excretion unchanged via lung (basis for breath alcohol test*).*It is a test metabolism of other drugs taken CYP450 2E1, which leads to significant to asses alcohol amount in the body, concurrently as (warfarin, increases in ethanol metabolism It usually used to drivers phenytoin). (Tolerance) & metabolism of other drugs as warfarin (Drug interactions) . Rate of elimination is zero-order *Acute : Only once, the patient not kinetic (not concentration- addicted. dependent) i.e. rate of elimination is the same at low and high concentration.(So we have to be careful to high dose or it will cause a toxic effect) Mechanism of action of alcohol: Genetic variation of alcohol Is a CNS depressants metabolism

Acute alcohol causes: Chronic alcohol leads to Aldehyde Dehydrogenase polymorphism

• Asian populations have genetic variation alcohol Enhancement the effect of up-regulation of NMDA receptors GABA (inhibitory in aldehyde dehydrogenase. & voltage sensitive Ca channels (acetaldehyde will not be converted to neurotransmitter) on its (Ca influx to nerve cells) leading acetate) GABA receptors in brain leading to CNS depression to alcohol tolerance & withdrawal symptoms (tremors, Inhibition of glutamate . They metabolized alcohol at slower rate than other populations. action (excitatory exaggerated response & neurotransmitter) on NMDA seizures). receptors leading to . Can develop Acute acetaldehyde disruption in memory, toxicity after alcohol intake consciousness, alertness. characterized by nausea, vomiting, dizziness, headache, vasodilatation, and facial flushing. *can use this as treatment, see later*

Acute actions of alcohol

In mild-moderate amounts In severe amounts

CNS depression 1. relieves anxiety, euphoria (feeling of 1. Severe CNS depression well-being). 2. Nausea, vomiting, aspiration of vomitus. 2. Nystagmus, slurred speech, impaired judgment, 3. Respiratory depression. 3. Sedation, hypnosis, loss of 4. CVS depression consciousness 5. Hypovolemia CVS depression 6. Hypotension 1. Myocardial contractility depression 7. Hypothermia 2. Vasodilatation due to vasomotor center 8. Coma, death. depression & direct smooth muscle

relaxation caused by acetaldehyde.

Chronic ethanol abuse (alcoholism) is associated with many complications

Liver Gastrointestinal system Cardiovascular System

• Reduction of • , hemorrhagic • Chronic can gluconeogenesis. esopahgitis, ulcer diseases, lead to cardiomyopathy • Fatty liver/ alcoholic (due to direct • Cardiac hypertrophy. steatosis toxic action on epithelium) • Congestive heart failure. • Hepatitis • Diarrhea • Hepatic : • Deficiency of vitamins. • Arrhythmia (due to jaundice, ascites, • Exacerbates nutritional potassium and magnesium depletion) bleeding, deficiencies encephalopathy. • weight loss, and • Hypertension: due to • Irreversible liver malnutrition. increased calcium & failure. sympathetic activity.

Acetaldehyde is more toxic than alcohol causing inflammation and fat cell proliferation

CNS Block Chronic ethanol abuse (alcoholism) is associated with many complications Hematological Endocrine CNS

• Hypogonadism: • Tolerance • Iron deficiency anemia 1- In women: ovarian • Physiological and (due to inadequate dietary dysfunction, amenorrhea, psychological intake & GIT blood loss). anovulation, dependence • Megaloblastic anemia: hyperprolactinemia, infertility. • Addiction:

(due to folate deficiency, 2- In men: gynecomastia, dopamine, malnutrition, impaired decreased muscle & bone mass, serotonin and folate absorption). testicular atrophy, sexual are • Hemolytic anemia. impotence due to inhibition of involved. • Bone marrow suppression luteinizing hormone (LH) , • Neurologic • Thrombocytopenia decrease in testosterone, disturbances (suppressing platelet estradiol, progesterone. • Wernicke-Korsakoff formation, prolong • Hypoglycemia & ketoacidosis syndrome bleeding times). due to impaired hepatic • Impaired production of gluconeogenesis & excessive vitamin-K dependent lipolytic factors, especially clotting factors leading to increased cortisol and growth prolonged prothrombin hormone. time. CNS Block Chronic ethanol abuse (alcoholism) is associated with many complications

Fetal Alcohol Syndrome Wernicke-

• Irreversible • It is a combined manifestation of 2 • Ethanol rapidly crosses placenta disorders: • Pre-natal exposure to alcohol causes: 1) Wernicke's encephalopathy: characterized • - Intrauterine growth retardation (due to by hypoxia) ocular disturbances - unsteady gait • Congenital malformation (teratogenesis): 1. Microcephaly (small head) changes in mental state as confusion, delirium, ataxia 2. Impaired facial development 3. Congenital heart defects 2) Korsakoff's psychosis: 4. Physical and mental retardation impaired memory & cognitive and

behavioral dysfunction.

• Cause: thiamine (vitamin B1) deficiency • Treated by: thiamine + dextrose- containing IV fluids.

CNS Block Alcoholism Tolerance

Chronic consumption of alcohol leads to tolerance That develops due to:

1) Metabolic tolerance (pharmacokinetic): due to induction of liver microsomal enzymes.

2) Functional tolerance (Pharmacodynamic): due to change in CNS sensitivity. Alcoholism withdrawal symptoms & it’s mangement

Alcoholism withdrawal symptoms (Autonomic hyperactivity due to super-sensitivity of Management of alcoholism withdrawal glutamate receptors & hypoactivity of GABA symptoms receptors ) Substituting alcohol with a long-acting drug then tapering the dose. craving for alcohol as (chlordiazepoxide, diazepam) or lorazepam that is preferable (shorter duration of action). Vomiting, thirst Fluoxetine Profuse sweating, severe tachycardia Clonidine & Propranolol: inhibits the action of exaggerated sympathetic activity Vasodilatation, fever a weak NMDA receptor antagonist & GABA activator, reduce psychic craving.

Delirium, tremors, anxiety, agitation, To prevent alcohol relapse: insomnia, hallucinations.

Grand mal seizures (after 7-48 hr alcohol therapy: Inhibits hepatic aldehyde cessation) Due to super-sensitivity of dehydrogenase, this will increase blood level of glutamate receptors & hypoactivity of GABA acetaldehyde. (As in Asian population) receptors are possibly involved. Acetaldehyde produces extreme discomfort, vomiting, flushing, tachycardia, dyspnea, palpitations & headache. Disulfiram-induced symptoms render alcoholics afraid from drinking alc Alcohol and drug interactions

• Inhibition of liver enzyme. • Decreases metabolism of e.g. bleeding with warfarin Acute alcohol use some drugs and increases their toxicities. • Induces liver microsomal enzymes. Chronic alcohol use e.g. warfarin, propranolol • Increases metabolism of drugs. Acetaminophen + alcohol  risk of hepatotoxicity. (chronic use)

 Increase in the risk of developing a major GI bleed or an ulcer. NSAIDs + alcohol

Alcohol suppresses gluconeogenesis > may increase risk for Hypoglycemia in diabetic patients.

Narcotic drugs (codeine and  risk of respiratory and CNS depression. methadone) + alcohol • Alcohol Lipophilic > rapid and easily absorbed > large V.D (distribute in all body). • Most of alcohol metabolized in the liver. • At low ethanol conc.(Acute alcohol),most of alcohol metabolism by alcohol dehydrogenase and minor metabolism by MEOS (microsomal ethanol-oxidizing system) mainly cyt-p450 (CYP2E1). Upon continuous alcohol use, this enzyme is stimulated and contribute significantly to alcohol metabolism. • Acetaldehyde in more toxic than ethanol • Asian populations have low Aldehyde Dehydrogenase >> metabolized alcohol at slower rate >> develop “Acute acetaldehyde toxicity” • Rate of elimination is zero-order kinetic (not concentration-dependent) i.e. rate of elimination is the same at low and high concentration. • Alcohol suppresses gluconeogenesis, which may increase risk for hypoglycemia in diabetic patients. • Acute acetaldehyde toxicity : vomiting, vasodilatation, flushing • Withdrawal symptoms: hypersensitivity, Autonomic hyperactivity, tremors, hallucinations, exaggerated response & seizures. • Hepatic cirrhosis: jaundice, ascites, bleeding, encephalopathy. • Fetal Alcohol Syndrome ( FAS ) : Microcephaly , Impaired facial development ,Congenital heart defects , Physical and mental retardation. • Wernicke's encephalopathy: ocular disturbances - unsteady gait, changes in mental state as confusion, delirium, ataxia • Korsakoff's psychosis: impaired memory & cognitive and behavioral dysfunction.

• Alcohol and drug interactions 1- warfarin + Acute alcohol = cause Bleeding 2- Phenytoin + Acute alcohol = toxicity 3- warfarin + Chronic alcohol = cause Drug interactions 4- Propranolol + Chronic alcohol = cause Drug interactions 5-Acetaminophen + alcohol (chronic use) = risk of hepatotoxicity. Alcohol can also increase the conversion of acetaminophen to toxic metabolites in liver 6- NSAIDs + alcohol = Increase in the risk of developing a major GI bleed or an ulcer. 7- Narcotic drugs (codeine and methahdone) + alcohol= risk of respiratory and CNS depression. • Treatment of Wernicke-Korsakoff syndrome : 8- Thiamine + dextrose-containing IV fluids. • Management of alcoholism withdrawal : 9-IV/ po Benzodiazepines as (chlordiazepoxide, diazepam) or lorazepam that is preferable (shorter duration of action): prevent irritability, insomnia, agitation & seizures. Avoid excessive dose that causes respiratory depression & hypotension. 10- Fluoxetine 11- Clonidine & Propranolol: inhibits the action of exaggerated sympathetic activity 12- Acamprosate: a weak NMDA receptor antagonist & GABA activator, reduce psychic craving. • To prevent alcohol relapse: 13- Disulfiram therapy: 250 mg daily, blocks hepatic aldehyde dehydrogenase, this will increase blood level of acetaldehyde. Alcohol : is a CNS depressants Pharmacokinetics of Mechanism of action

Actions of alcohol: ethanol of alcohol

Every thing go down inhibits CYP450 2E1 In mild-moderate amounts warfarin, phenytoin +Acute • Enhancement of GABA >> • CNS depression(e.g: euphoria, loss of consciousness) alcohol = decrease CNS depression • CVS depression(e.g: Vasodilatation caused by metabolism of alcohol and • Inhibition of glutamate acetaldehyde) the drugs, increases their on NMDA receptors >> In severe amounts • Severe CNS depression (e.g:respiratory toxicities e.g. bleeding with disruption in memory, depression, coma.)

Acute alcohol Acute warfarin consciousness, alertness • CVS depression • Hypotension ( Enzyme Inhibitor ) Inhibitor Enzyme ( • Coma, death.

.Tolerance, dependence, addiction, behavioral induces liver microsomal changes enzyme CYP450 2E1 .Liver: hepatic cirrhosis & liver failure. .CVS: hypertension, myocardial infarction warfarin, propranolol + .CNS: cerebral atrophy, cerebellar degeneration, chronic alcohol = significant up-regulation of NMDA and peripheral neuropathy. Wernicke increases in ethanol receptors & Ca influx to encephalopathy or Korsakoff psychosis may occur. metabolism (Tolerance) & nerve cells >> tolerance & .GIT system: irritation, inflammation, infections, metabolism of other drugs as bleeding, Deficiency of vitamin s ,nutritional withdrawal symptoms deficiencies

Chronic alcohol Chronic warfarin (Drug interactions). .Endocrine system: gynecomastia & testicular ( Enzyme Inducer ) ) Inducer Enzyme ( atrophy .Hematological disorders ( all kinds of anemia), neoplasia. Quiz yourself Q3:Which of the following Q1: Asian man drink alcohol Q2: If you have diabetic and metabolic alterations may and come to you Suffers alcohol adducted patient , be associated with chronic Q4: Which of the following from vomiting, what you should alcohol abuse? agents is an inhibitor of vasodilatation, flushing in recommend to him? A) Hyperglycemia aldehyde dehydrogenase? his face what is the cause of A) Decrease the dose of B) Increased serum A) Fomepizole his symptoms? Antidiabetic drug concentration of B) Ethanol A) Korsakoff's psychosis: B) increase the dose of phosphate C) Disulfiram B) Acute acetaldehyde Antidiabetic drug C) Severe loss of potassium D) Naltrexone toxicity C) Stop the Antidiabetic and magnesium C) Hepatic cirrhosis drug D) Decreased serum D) Fetal Alcohol Syndrome D) There is no difference concentration of sodium

Q7: We have an alcoholic Q5: What kind of deficiency Q6: Alcohol diminish the patient with a family Q8: Wernicke-Korsakoff developed in chronic production of which history of alcohol abuse, syndrome develops due to alcoholics? : vitamin? : what’s the best drug to which deficiency? : A) Folate deficiency A) Vit-C reduce his drinking habits? A) Iron Deficiency B) Iron deficiency B) Vit-B12 A) Fluoxetine B) Thiamin Deficiency C) Vit-B12 deficiency C) Vit-K B) Clonidine C) Vit-B12 deficiency D) A & B D) Vitamin A deficiency C) Propranolol D) Vitamin A deficiency D) All above

Answers: 1-B,2-A,3-C,4-C,5-D,6-C,7-D,8-B Raneem Alotaibi Ahmed Aldakhil Awatif alenazi Contact us for any questions Hanan Aldossari or comments : Jumanah Albeeybe

[email protected] Noura Alrayes Nada Bin dawood @pharma_433

We hope that we made this lecture easier for you Good Luck ! CNS Block