Alcohol

ALCOHOLPHARMACOKINETICS ANDPHARMACODYNAMICS;DRUG INTERACTIONS AND PHARMACOTHERAPEUTICS

DR.AYON BHATTACHARYA

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What is Alcohol?

• Hydroxy derivatives of aliphatic hydrocarbons.• Small polar molecule,nonionized with both lipophilic

and hydrophilic characteristics.• C6 H12 O6 2CO2 +2C2 H5 OH• UNDISTILLED ALCOHOL -BEER - 4-6% v/v -WINE – 10-15% v/v• DISTILLED SPIRITS (Rum, Vodka , Gin ,Baijiu , Tequila ,Whisky ,Brandy ,Slivovitz ,Soju the alcoholic about 40% higher)

YEAST

ZYMASE

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PHARMACOKINETICS

• ABSORPTION : -Oral cavity ,Stomach and small intestine. -Peak blood level occurs in 30 mins after ingestion of alcohol. -First pass metabolism occurs in the liver and stomach by Alcohol dehydrogenase. -Lower blood ethanol levels (BELs) by oral route

compared to i.v route.

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FACTORS AFFECTING THE RATE OF ABSORPTION OF ALCOHOL(ETHANOL)

• The rate ,volume ,and concentration of alcohol consumed.

• The presence or absence of food in the stomach

• Interaction with medications like drugs interfering with the gastric motility.

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DISTRIBUTION• 0.5-0.7L/Kg• Hydrophilic ,distributed along the distribution of the total body

water.• Distributed in tissues with high water content and more blood

supply (Brain ,skeletal muscle)• Body composition and sex plays a role in the distribution of the

alcohol.• Females have a higher blood alcohol level than male : -Smaller Lean body mass and blood volume than males. -Lower first pass metabolism by gastric ADH than males

http://www.webmedcentral.com/article_view/3291 4

MEDICOLEGAL IMPLICATIONS

• Ratio of ethanol in end expiratory alveolar air and the blood is relatively

constant.• BELs can be measured in the expired air.• The partition coefficient for ethanol between blood and alveolar air is 2000 : 1.• BELs is dependent on other factors like sex, rate of drinking, body weight, rate of metabolism, stomach

emptying. 5

PHARMACOKINETICSELIMINATION

90-98%

RATE LIMITING STEP

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GENETIC FACTORS INFLUENCING METABOLISM OF ALCOHOLS

ADH1B ADH1B

ADH1B

ADH1B ALDH-2

ALDH-2

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ADH1B

ADH1C

ELIMINATION

• Metabolism follows zero order kinetics (8-12ml of absolute alcohol/hour)

• 98% of alcohol is oxidized in the liver.• <10% escapes metabolism.• Excretion occurs in kidney and lungs

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PHARMACODYNAMICS

CENTRAL NERVOUS SYSTEM :SEVERITY

UNCONTROLLED MOOD SWINGSEMOTIONAL OUTBURST/VIOLENT BEHAVIOUR

CNS FUNCTIONS GET IMPAIRED

GENERAL ANAESTHESIA

DEATH

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CENTRAL NERVOUS SYSTEM

ACUTE ALCOHOLISM• Ethanol adaptation to acute

doses act opposite to chronic doses

CHRONIC ALCOHOLISM• Shrinkage of brain; loss of

both grey and white matter• Frontal lobe the most

sensitive to damage by alcohol.

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• ROLE OF NEUROTRANSMITTER SYSTEMS : •Acute ethanol intake

-Activation of the dopaminergic pathways -Increase in synaptic dopamine -Alteration in the dopamine activity in the ventral tegmental area(VTA) plays a role in euphoria and reward circuits in the brain. -Dopaminergic activity in the VTA is further augmented by opioid receptors. -Acute ethanol ingestion causes release of β endorphines which act on the μ receptor and increases dopamine release. -Increase in 5-HT in synaptic space, also plays a role in the dopaminergic systems. -Activation of cannabinoid receptor affects release of DA, GABA, Glutamate.

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• CHRONIC ALCOHOLISM :- Activation of both D2 and D4 receptors hence

the desire for alcohol intake and relapse symptoms are higher.

- Upregulation of 5 HT receptors. Higher alcohol intake and lower levels of reaction to alcohol


• ROLE OF NEUROCHEMICAL SYSTEMS :Alcohol disturbs the balance between the

excitatory and inhibitory influences in the brain.

Ethanol has predominant effects on the ligand gated ,voltage gated ion channels and GPCR systems

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• Alcohol causes the enhancement of GABA and glycine mediated inhibition.

• In acute alcoholism there is increase in GABA release ,in chronic alcoholism expression of genes impacting on the GABA subunits.

• This results in sleepiness ,muscle relaxation.• Intoxication is viewed as a GABA rich state

while withdrawal as GABA deficiency.

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ROLE OF NEUROCHEMICAL SYSTEM• Nicotinic Ach receptors :-Increases Ach and dopamine release.• NMDA receptors : -Inhibited.• Inhibition of adenosine transport.• Neuronal excitability is reduced by alcohol

acting on the voltage gated Ca+2 channel.14

SIGNS AND SYMPTOMS OF ALCOHOLISM

CHRONIC ALCOHOLISM : Anterograde amnesia called as Alcoholic blackouts. Disruption of sleep architecture, nightmares, rapid eye

movements Hangover the next morning Alcoholic dementia Thiamine and nutritional deficiencies Wernicke’s encephalopathy ,Korsakoff’s psychosis Depressive symptoms, suicidal thoughts ,panic attacks Auditory hallucinations ,paranoid delusions (3%)

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SIGNS AND SYMPTOMS OF ACUTE ALCOHOLISM

• Confusion, unpredictable behaviour ,stupor• Sudden lapse between semi-consciousness

and unconsciousness.• Amnesia• Vomiting• Seizure• Respiratory depression(<8 breaths/min)• Cold clammy skin due to insufficient oxygen

http://en.wikipedia.org/wiki/Alcohol_intoxication

ALCOHOL LEVELS AND EFFECT ON CNS

• 50-100 Mg/dl- Relief of anxiety, sedation , loss of inhibition ,impaired judgement.

• 100-200mg/dl-Gross drunkeness characteristics like slurred speech ,ataxia , mental clouding,impaired motor functions

• 200-300 mg/dl- Emesis and stupor• 300-400 mg/dl –Respiratory and cardiovascular

depression , coma• >500mg/dl -Lethal

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NEUROTOXICITY

WERNICKE KORSAKOFF SYNDROME• Thiamine deficiency• Symmetric peripheral nerve injury, degenerative

changes• Paralysis of external ocular muscles ,ataxia ,

confused state• Progressive in nature • Chronic disabling memory disorder called as

Korsakoff’s psychosis.

DEMONSTRATION OF ALCOHOL ON MOTOR DRIVING

LOSS OF SKILLON ALCOHOLINTAKE

INABILITY TO DEAL WITH CRISIS

ACCIDENTS

INCREASED DISTRACTABILITYOVERCONFIDENCE

EXCESSIVE CAUTIONMORE STEERING WHEEL MOVEMENTS

BAD JUDGEMENTINACCURATE CORNERING

TENDENCY TO DRIVE IN THE MIDDLE OF ROADDELAYED RECOVERY FROM DAZZLELACK OF COLOUR DISCRIMINATION

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CARDIOVASCULAR SYSTEM

CARDIOVASCULAR SYSTEM :Ethanol > 3 drinks/day increases the chance of

heart disease (10-20mmol/l)“French paradox”Prospective cohort studies have found that

persons consuming 1-20gm/day to moderate 21-40gm/day lowered the rate of Angina

pectoris ,myocardial infarction, PVD.

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THE MECHANISM OF THE CARDIOPROTECTIVE EFFECTS OF ALCOHOL IN LOW DOSES :

• Increase in HDL levels, binds to cholesterol and returns it to the liver.

• Prevents the accumulation of cholesterol in the arterial wall

• Increase in tissue plasminogen ,helps in dissolution of clot.

• Decrease in fibrinogen levels• Inhibition of platelet activation.

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Alcohol raises systolic and diastolic Blood pressure 5-11% prevalence of HTN in alcoholism (MEN > WOMEN) >30 gms alcohol/day associated with 1.5-2.3 mm rise in

diastolic and systolic BP. Small doses :cutaneous and gastric vasodilation Moderate doses :causes tachycardia and mild rise in BP Large doses :Marked fall in BP Significant myocardial depression (>100mg/dl)

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ACUTE ALCOHOL INTAKE


Cardiac arrhythmias seen with ethanol is -Supraventricular tachycardia -Atrial fibrillation -Atrial flutter -Ventricular Tachycardia.Mechanisms for this arrhythmias are prolongation of QT

interval, prolonged ventricular repolarization ,sympathetic stimulation.

Patient with chronic alcoholism are resistant to cardioversion ,digoxin ,and Ca+2 channel blockers 21

CHRONIC ALCOHOLISM


Cardiomyopathy due to toxic effect of alcohol on cardiac and skeletal muscles.

Decrease in cardiac contractility.Women at greater risk than men40-50% of people with alcohol induced

cardiomyopathy die within 3-5 years.

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• STROKE is caused by consumption of more than 40 gm/day of ethanol.

• Haemorrhagic and ischaemic stroke• CAUSES : -Cardiac arrhythmias and thrombus formation -High BP and subsequent cerebral artery degeneration -Acute rise in BP and alteration of cerebral artery tone -Head trauma

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SKELETAL MUSCLES

Decreased muscle strengthDecreased muscle protein synthesisMuscle fibre damage ,muscle atrophy, skeletal

myopathy Investigations in the patient show -Increase in creatinine kinase -Reduction of serum carnosinase -Electromyographical changes

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BODY TEMPERATURE

The person feels warm due to cutaneous and gastric blood flow.

Increased sweatingOn large doses the central temperature

regulating mechanism becomes depressedIn low temperature this action of alcohol is

more pronounced.

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GASTROINTESTINAL SYSTEM

Esophagus – Alcohol causes esophageal reflux, Barrette’s esophagus, traumatic rupture of

esophagus. -Smoking further increases the chances for

cancer by 10% -Cause :Due to decrease in peristalsis Lower esophageal sphincter pressure

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GASTROINTESTINAL SYSTEM STOMACH : -Beverage containing more than 40% alcohol causes direct

toxic effect on the gastric mucosa. -Back diffusion of acid from the gastric lumen into the mucosa -Disrupts the gastric mucosal barrier. -Exacerbates acid peptic disorder. -Acute alcohol intake shows gastric erosions and petechial

haemorrhage. -Chronic alcoholism-Chronic gastritis -Acts synergistically with H.Pylori- delays healing.

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INTESTINE :Chronic diarrhoea and malabsorptionRectal fissure and pruritis aniCause : -Structural and functional change in the small intestine. -Villi gets flattened -Digestive enzyme levels are decreasedReversible on abstinence

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PANCREAS :Acute and chronic pancreatitis.Causes : - Direct toxic metabolic effect of alcohol on

pancreatic acinar cells.-Altered permeability of pancreatic epithelial cells -Formation of protein plugs and CaCO3 stonesHyperglycemia

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LIVER :FATTY LIVER HEPATITIS CIRRHOSIS

Hepatic cirrhosis is the end stage liver disease with fibrosis ,regenerating hepatocytes not in tune with the blood and biliary system.

Diversion of portal blood causing esophageal varices bleeding.

15-30% of alcoholics develop liver disease.

REVERSIBLE IRREVERSIBLE

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LIVER:Cause : Due to fatty acid release from adipose

tissue (increased stress ,sympathetic discharge

-Impaired fatty acid oxidation

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REPRODUCTIVE FUNCTIONS

REPRODUCTIVE ACTIONS :MALEImpotence seen in 50% of chronic alcoholicsTesticular atropyGynaecomastia (increased response to

estrogen and increased metabolism of testosterone)

Cause :Direct toxic effect of alcohol on leydig cells

REPRODUCTIVE ACTIONS

FEMALELoss of libidoVaginal drynessMenstrual cycle abnormalitiesOvaries small without follicular developmentFertility rates are lower for alcoholic femalesCo-morbid conditions like anorexia nervosa

aggravate the problem

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HAEMATOLOGICAL AND IMMUNOLOGICAL EFFECTS

Microcytic ,macrocytic and sideroblastic anaemias.Alcohol affects granulocyte and lymphocytesLeucopenia and decreased immunoglobulin

productionPoor resistance to infections like Klebsiella

pneumonia , listeria , TB ,HIVAltered function of lymphoid cells and disruption of

cytokine regulation33

OTHER ACTIONS :

Vitamin and mineral deficienciesIn acute alcoholism alcohol inhibits

vasopressin hence diuresis but later the person develops less urine output.

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ETHANOL IN PREGNANCY

Incidence 3/1000 live birth

1970,term fetal alcohol syndrome30% of children born to alcoholic mother

Alcohol related neurodevelopemental disorder.(ARND)[More common]

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TOLERANCE AND DEPENDANCE

Tolerance is the reduced behaviour or physiological response to the same dose of ethanol.

Dependence is elicitation of a withdrawal syndrome when alcohol consumption is terminated. It is of two types :

-Physical and psychologicalSymptoms HYPEREXCITABILITY SEIZURES TOXIC PSYCHOSIS

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DELIRIUM TREMENS

TOLERANCE AND DEPENDENCE

CAUSES :Change in the synaptic and intracellular signalling Increase in the NMDA receptor function after the

chronic alcoholism phase leading to hyperexcitability and neurotoxicity

Impairment of dopaminergic system and hence increase in alcohol consumption to regain activation

Prefrontal cortex is sensitive to alcohol damage , hence the process of decision making and emotions are compromised in alcoholics

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DRUG INTERACTIONSMEDICATIONS CAUSING DISULFIRAM LIKE REACTIONS:ANALGESICS –Phenacetin PhenylbutazoneANTIBIOTICS-• Cefoperazone • Cefotetan • Chloramphenicol • Griseofulvin• Isoniazid • Metronidazole • Nitrofurantoin • Sulfamethoxazole • Sulfisoxazole

CARDIOVASCULAR MEDICATIONS Isosorbide dinitrate (nitrates) Nitroglycerin

DIABETES MEDICATIONS Chlorpropamide (sulfonylureas) Glyburide Tolazamide Tolbutamide

ANTICOAGULANTSWarfarin

DRUG INTERACTIONSPHARMACOKINETIC

ANALGESICS ASPIRINACETAMINOPHEN

•Increases gastric emptying•Inhibit gastric ADH•Alcohol metabolizes acetaminophen into a toxic metabolite causing liver damage•Increases ethanol bioavaillability

ANTIBIOTICS ERYTHROMYCINISONIAZID

•Increases gastric emptying•Enhances isoniazid induced liver toxicity

ANTICONVULSANTS PHENYTOIN •Alcohol causes phenytoin breakdown•Phenytoin induces microsomal enzymes

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DRUG INTERACTIONSANTICOAGULANTS WARFARIN •Acute alcoholism

decreases warfarin metabolism. Chronic alcoholism increases metabolism of warfarin.•Disulfiram reaction

ANTIDIABETIC AGENT ChlorpropamideGlyburideGlipizideTolbutamidemetformin

•Hypoglycemia•Chlorpropamide,glyburide ,tolbutamide causes disulfiram like reaction•Metformin increases levels of lactic acid in blood after alcohol consumption

BARBITURATES Phenobarbital •Increase in barbiturate metabolism by cytochrome P450•Enhances sedative, hypnotic effect on CNS

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DRUG INTERACTIONSMUSCLE RELAXANTS Carisoprodol

Cyclobenzaprine•Enhances the impairment of physical abilities and sedation•Carisoprodol produces a opiate like” high” when taken with alcohol. Metabolized to meprobamate, abused as street drug

HISTAMINE H2 RECEPTOR ANTAGONIST

CimetidineRanitidine

•INHIBIT ADH IN THE STOMACH•INCREASE GASTRIC EMPTYING

IMMUNE MODULATORS methotrexate Liver damage in association with alcohol

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DRUG INTERACTIONSNSAIDS Ibuprofen

NaproxenDiclofenac

Alcohol increases the risk of gastrointestinal bleeding

SEDATIVES AND HYPNOTICS

Chloral hydrateMeprobamate

Alcohol inhibits the metabolism and enhances the sedation, drowsiness

TRICYCLIC ANTIDEPRESSANTS

AmitryptalineImipramineDesipramineClomipramine

•Enhances the sedation •Orthostatic hypotension

VITAMINS Vitamin AVitamin D

•Vitamin A should be monitered when taken with alcohol to prevent retinol induced hepatoxicity•Vitamin D hydroxylation is hampered by the liver damage of alcohol

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DRUG INTERACTIONSPHARMACODYNAMIC

ANTIHISTAMINICS Diphenhydramine Chlorpheniramine ClemastineHydroxyzine Promethazine

•Enhances the drowsiness, sedation, decreased motor skills.(More in elderly people)

BARBITURATES Phenobarbital • Enhances sedative, hypnotic effect on CNS

BENZODIAZEPINES AlprazolamChlordiazepoxide

Alcohol enhances the effect of these agents on the CNS.

MUSCLE RELAXANTS CarisoprodolCyclobenzaprine

•Enhances the impairment of physical abilities and sedation

OPIOIDS CodeineMorphinePropoxyphene ,Fentanyl

Enhances the effect like sedation,drowsiness, and decreased motor skills

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DRUG INTERACTIONS PHARMACODYNAMIC

SEDATIVES AND HYPNOTICS

Chloral hydrateMeprobamate

Alcohol inhibits the metabolism and enhances the sedation,drowsiness

TRICYCLIC ANTIDEPRESSANTS

AmitryptalineImipramineDesipramineClomipramine

•Enhances the sedation •Orthostatic hypotension

CORTICOSTEROIDS PrednisoloneDexamethazone

•Aggravate the stomach irritation•Psuedo cushing’s syndrome

BRONCHODILATORS Theophyllin Aminophyllin

•Impair mucociliary clearance•Increased chance of infection

LIPID LOWERING AGENTS Atorvastatin •Aggravate liver damage44

DRUG INTERACTIONSPHARMACODYNAMIC

ANTIBIOTICS SULFONAMIDES Disulfiram like reaction

MAO INHIBITORS Moclobemide Hypertensive crisis

PHARMACOTHERAPEUTICSOF ALCOHOLISM

CLASSIFICATION OF DRUGS USED IN ALCOHOLISM

CLINICOPATHOLOGICAL CLASSIFICATION

AVERSION THERAPYa)Disulfiramb)Fomepizole

ANTI-CRAVING DRUGS a)Acamprosate b)Naltrexone c)Nalmefene d)Newer drugs under clinical trials -Topiramate -Varenicline -Rimonabant

PREVENTION OF WITHDRAWALSYMPTOMS-BENZODIAZEPINES Diazepam ,Chlordiazepoxide

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CLASSIFICATION OF DRUGS USED IN ALCOHOLISM

PHARMACOLOGICAL CLASSIFICATIONA) Alcohol dehydrogenase inhibitor - FomepizoleB) Aldehyde dehydrogenase inhibitor -DisulfiramC) Partial agonist of NMDA Receptor -AcamprosateD) Opioid receptor Antagonist -Naltrexone -NalmefeneE ) Newer Drugs (under clinical trials) -Cannabinoid receptor Inverse agonist (CB1 )-

Rimonabant -Nicotinic Receptor Partial agonist- Varenicline -AMPA/Kainate Receptor Antagonist- Topiramate -5HT3 Receptor Antagonist- Ondansetron 2

WHY DO PEOPLE DEVELOP ADDICTION ?

• The epidemiological triad plays an important role here.

A AGENT

(DRUG)

HOST(USER)

ENVIRONMENT

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FACTORS AFFECTING ADDICTION

• Agent – Reinforcement of the drug - Cost - Purity - Mode of administration - Rapidity of onset of action

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FACTORS AFFECTING DRUG ABSORPTION

• HOST : -Genetic polymorphism of enzymes -Children of Alcoholics -Innate tolerance -Impaired metabolism -Psychiatric disordersPeople anxious/shy Relief on taking alcohol

Repeated usetolerance

Compulsive uncontrolled Drug use

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FACTORS AFFECTING DRUG ADDICTION

• ENVIRONMENTAL FACTORS : - Illegal drug use is due to the stringent laws and societal norms - Taking drugs : Rebellion against authority , Role models, Paucity of other options of pleasure , Unemployment, Low educational status

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PHARMACOTHERAPEUTIC STRATEGIES FOR TREATING ALCOHOLISM

• Detoxification• Psychosocial Aspect -Self help and Mutual Support Programs -Moderation Management -Cognitive Behavioural Therapy (CBT)• Medications to prevent long term dysphoria• Treatment of co-occuring Psychiatric

symptoms

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DETOXIFICATION

• It is a process of gradually decreasing the dose of the drug of abuse to prevent withdrawal symptoms.

• Reduces the craving ,prevent the relapse from abstinence and the harmful use of alcohol.

• Strategy for detoxification is : -To taper the dose of the drug

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DETOXIFICATION

• Aversive therapy : Disulfiram• Block the effect of the drug of abuse : - Naltrexone - Recent research is being done on antiepileptic

drugs like Topiramate , which suppresses the CNS hyperactivity due to withdrawal from alcohol

• Long acting agents for maintainance medications

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SYMPTOMS DUE TO ALCOHOL WITHDRAWAL

• Alcohol craving• Tremors and irritability• Nausea• Sleep disturbances• Tachycardia• Hypertension• Sweating• Seizures• Visual hallucinations• Delirium Tremens

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TREATMENT FOR DETOXIFICATION

• Short acting Benzodiazepines like Oxazepam used at doses 15-30 mg every 6-8 hrs.

• Long acting Benzodiazepines can also be used unless liver failure.

• Anticonvulsants like Carbamazepine has also been effective in Alcohol withdrawal

• Drawback for both these drug groups are subjective symptoms(hallucinations) are not relieved.

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SELF HELP AND MUTUAL SUPPORT PROGRAMS

ALCOHOL ANONYMOUS (AA)• International mutual aid fellowship founded in 1935.• AA states “Its members primary purpose is to stay sober and help other

alcoholics achieve sobriety “.• The members and the group remain

anonymous from public media.

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MODERATION MANAGEMENT

• Here the principle is moderation rather than abstinence.

• Ineffective in dependent individuals• Recommended only in “problem drinkers”

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TREATMENT OF DYSPHORIC SYMPTOMS IN ALCOHOLISM

• Acamprosate could be a good option in this context.

• Alcohol consumption leads to hyperactive glutaminergic system and acamprosate reverses it

• But only few studies have shown acamprosate to be efficacious in this condition

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TREATMENT OF PSYCHIATRIC SYMPTOMS IN ALCOHOLISM

• Depressed mood, anxiousness, mood instability is seen in abstinent patients

• SSRI’s caused early onset alcoholics to drink more often, and with worser outcomes

• Treatment of abstinent patients with mood stabilizers and antipsychotic medications is beneficial.

• Desipramine a MAO Inhibitor and Fluoxetine a SSRI’s have shown to reduce drug craving.

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DISULFIRAM

ERIC JACOBSEN & JENS HALD MEDICINALCO LABORATORY

1881-M.Grodzki C10 H20 N2 S4

1901-Used in Rubber industry for vulca – nization of rubber.1937-E.E .Williams1945-Disulfiram for a new indication1948-Jacobsen addressed the meeting of British Pharmacological society on Disulfiram1948-1953 - 140 research papers were published 16

DISULFIRAM

TETRAETHYLTHIURAM DISULFIDE

•Prodrug•High lipid solubility•Highly distributed in the fat depots of our body.•More bioavailable with food•Rapidly metabolized to diethyldithio- carbamate (DDC)in the liver DDC Me-DDC Diethylthiocar baminic acid methy ester(Me-DTC)•Concentration of Me-DTC reaches maximum in 4 hrs

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CONGENERS OF DISULFIRAM

• Congeners of disulfiram like : - Cyanamide - Coprinus atramentarius(fungus) - Sulphonylureas - Metronidazole - Cetain cephalosporins

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DISULFIRAM

• Enzyme inhibiting effect is seen after 3 doses• Half life of Me-DTC-10hrs• ALDH inhibiting effect last longer,the effect can

persist for 10-14 days after stopping the drug• Disulfiram and its metabolites inhibit many

enzymes with sulfhydryl group.• Inhibit hepatic CYPs---Phenytoin, Warfarin• Excretion occurs through kidneys and through

lungs as carbon disulfide.

http://www.medsafe.govt.nz/profs/datasheet/a/Antabusetab.pdf19

DISULFIRAMMECHANISM OF ACTION

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DISULFIRAM MECHANISM OF ACTION

1) Inhibits both the mitochondrial and cytosolic forms of Aldehyde dehydrogenase enzyme.

• Irreversible inhibition• Accumulation of Acetaldehyde leading to

distressing symptoms :Hot flushed face (<10 mins),pulsatile headache, Respiratory difficulty ,nausea ,vomiting ,sweating , orthostatic syncope, chest pain ,hypotension, confusion ,blurred vision.

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DISULFIRAMMECHANISM OF ACTION

2 ) Recent research has found disulfiram to reduce the dopa β-hydroxylase

• Increase in brain dopamine levels• This action has a basis for its recent use in

cocaine users

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PRECAUTIONS OF USING DISULFIRAM

• Disulfiram itself is non toxic• DISULFIRAM + ALCOHOL = TOXIC• Should not be given to patients within 12-24

hours of alcohol consumption• The patient should not take alcohol from

atleast 2 week to 3 weeks

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DOSAGE OF DISULFIRAM

• 200,250,500 mg tablets• Initial phase maximum 500 mg for 1-2 weeks ,

then maintainance at 125-500 mg/day, usually at morning

• Sensitization to alcohol lasts for 14 days.

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ADVERSE EFFECTS OF DISULFIRAM

• Drowsiness• Headache, • Acneform eruptions• Urticaria• Tremors• Weakness• Metallic or garlic taste in the mouth• Disulfiram neurotoxicity is rare• Peripheral neuropathy• Psychosis

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DRUG INTERACTIONSMEDICATIONS CAUSING DISULFIRAM LIKE REACTIONS:ANALGESICS –Phenacetin PhenylbutazoneANTIBIOTICS-• Cefoperazone • Cefotetan • Chloramphenicol • Griseofulvin• Isoniazid • Metronidazole • Nitrofurantoin • Sulfamethoxazole • Sulfisoxazole

CARDIOVASCULAR MEDICATIONS Isosorbide dinitrate (nitrates) Nitroglycerin

DIABETES MEDICATIONS Chlorpropamide (sulfonylureas) Glyburide Tolazamide Tolbutamide

ANTICOAGULANTSWarfarin

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FOMEPIZOLE

• 4-Methyl Pyrazole (C4 H6 N2 )• Water soluble• Volume of distribution is 0.6 l/kg to 1.02 l/kg.• Metabolized to 4-carboxy pyrazole and 4 hydroxymethyl

pyrazole with their respective N-glucoronide conjugates.• Excreted in urine• Follows mixed order kinetics.• Ethylene glycol and methanol poisoning• Nausea, vomiting ,metallic taste, dizziness

http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a306cd11-9acf-45f1-91ec-9fef2b08fdb1

ROLE OF NEUROTRANSMITTERS IN ALCOHOLISM

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DA

μ

5HT2A

CB1

CB1

GABAA

NN

NMDA

ROLE OF NEUROTRANSMITTERS IN ALCOHOLISM

ACUTE ALCOHOL INTAKE• Activation of reward circuit in the

brain resulting in increase in dopamine release

• Stimulation of μ receptors resulting in dopamine release and endorphines

• GABA rich state(GABA –mimetic)• Inhibition of NMDA receptor

functions• Altering the 5HT receptor pathways• Increase in ACh in the VTA and

subsequent release of DA.

CHRONIC ALCOHOL INTAKE• Dopaminergic release

pathways impaired• Upregulation of 5HT

receptor• GABA deficient state• Stimulation of NMDA

receptors

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ACAMPROSATE

• N-acetylhomotaurine• Known as the “Anti-craving Drug”• Efficacy same as naltrexone• Not metabolized by liver• No drug interactions• Excreted by kidneys (90%)• Half life of 18 hrs after oral administration

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ACAMPROSATE

• Mechanism of action not clear - Increase in the NMDA receptor function after the

chronic alcoholism phase leads to hyperexcitability and neurotoxicity during withdrawal.

- Blocks the excitatory activity of the NMDA glutamate receptor and enhance the inhibitory system GABAA receptor

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USES OF ACAMPROSATE

WHOM SHOULD BE GIVEN ACAMPROSATE :• Patient having anxiety during their abstinence

period.• Patients trying to abstain from alcohol. -Reduces the number of drinks /day• Recent studies have shown Acamprosate to

have neuroprotective actions -Detoxification

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ACAMPROSATE

• ADVERSE EFFECTS :- Gastrointestinal System

Nausea, vomiting ,diarrhoea. - Rash• CONTRAINDICATIONS -Renal impariment • DOSAGE : -Patients >60kg-two tablets (333mg) thrice a day. - Patients <60mg-two tablets in morning,one in midday and one at night

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NALTREXONE• Highly selective opioid receptor antagonist•Well absorbed after oral administration•Rapid first pass metabolism •Half life – 10 hrs•High bioavailability and longer duration of action(>24hrs)•Mechanism of action : -Blocks the dopaminergic reward circuit in the brain -Hence the pleasurable effect of alcohol is not felt•Naltrexone maintains abstinence -Reducing the urge to drinking -Increased control during slip periods•Drawback of naltrexone is that it does not prevent relapse

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NALTREXONE

• It works best in conjunction with psychosocial therapy.

• Dosage : Given for detoxification at 50 mg/day for several

months• Adverse effects : Nausea, liver damage• Adherence of the regimen is important for the

benefits of naltrexone therapy

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NALMEFENE

• Opioid antagonist• New drug completed phase 3 trials for its use in

alcoholics• Dose 50- 150 mg/day p.o or monthly 380 mg injection

once a month.

ADVANTAGES OVER NALTREXONE :1. Greater oral bioavilability(<41%)2. Longer duration of action3. Lack of dose dependent liver toxicity

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ALCOHOLS AND ITS POISONING

• Four major alcohols that human beings come in contact to are :

-Ethanol- Consumable -Methanol -Ethylene Glycol -Isopropanolol

Non-consumable

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ALCOHOL SOURCES

• Ethanol-In commercial alcoholic drinks.• Methanol –”Wood Alcohol”,solvent in paint

products,windshield washing fluids ,antifreeze• Ethylene Glycol-coolent and preservative,

polishes and detergents.• Isopropanol-Rubbing alcohol ,solvent ,skin

and hair products, paint thinners, antifreeze

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ACUTE ALCOHOL INTOXICATION

• Airways• Breathing• Circulation• Defibrillation• Exposure• Functional impairment restoration

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ACUTE METHANOL INTOXICATION

CLINICAL FEATURES :• Symptoms take 12-18hrs to develop• Time taken for symptoms to arise increases if

ethanol is taken along with it• CNS - CNS Depression - Visual disturbances (“Looking at a

snowstorm”) GIT – Nausea ,Vomiting ,abdominal pain• Lethal dose of methanol is 1-2 ml/kg

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TREATMENT :• General Supportive measures• Folate 50 mg I.V every 4 hours• Sodium Bicarbonate to correct acidosis• Fomepizole 15 mg/kg loading dose followed by 10

mg/kg every 12 hours for 4 doses.• Fomepizole not available then Ethanol 0.6 gms/kg i.v given as loading dose followed by

continuous infusion of 0.11 gm /kg/hr

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• Serum glucose to be monitored and treated accordingly

• Dialysis is indicated when a)Signs and symptoms of significant toxicity b)High anion gap metabolic acidosis c)Methanol or Ethylene Glycol levels above 20

mg/dl d)Ocular toxicity for methanol and nephrotoxicity

for Ethylene Glycol41


• Dialysis can be given along with ethanol or fomepizole till the methanol level is 0 and acidosis is corrected.

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ACUTE ETHANOL TOXICITY

• 50-100 Mg/dl- Relief of anxiety, sedation , loss of inhibition ,impaired judgement.

• 100-200mg/dl-Gross drunkeness characteristics like slurred speech ,ataxia , mental clouding, impaired motor functions

• 200-300 mg/dl- Emesis and stupor• 300-400 mg/dl –Respiratory and cardiovascular

depression , coma• >500mg/dl -Lethal

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ETHANOL INTOXICATION

• Vitamin B1 –Thiamine 50-100mg i.v or p.o daily for 7 days

• In presence of seizures- -Low potency Benzodiazepines Diazepam 10 mg i.v or p.o 4-6hrs Chlordiazepoxide-25 mg p.o 4-6 hrs• Serum glucose should be monitored.• Dialysis

44

ETHANOL INTOXICATION

• Patients with prolonged CNS depression require

admission• Patients asymtomatic for 6-8 hrs are discharged• Recovery : - Education ,Counseling ,vocational rehabilitation,

self help groups like Alcohol Anonymous - Prevent relapse - Psychiatrist referral

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ACUTE ISOPROPANOL INTOXICATION

• In case of isopropanol poisoning -Treatment as per ethanol poisoning -The CNS depressant actions are more

pronounced -Fruity odour of ketones in the patients breath. -GI Bleed more severe (Haemorrhagic gastritis) -Dialysis is indicated when ispropanol levels

are >400mg/dl

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ACUTE ETHYLENE GLYCOL POISONING

• ETHYLENE GLYCOL :Three phases after poisoning : -Within 12 hrs-CNS effects predominate -12-24 hrs -Cardiopulmonary effects elevated HR,BP -24-72 hrs-Renal impariment ,Hypocalcaemia• Treatment:-Pyridoxine 100mg and thiamine 100mg i.v or i.m every day - Calcium replacement - Haemodialysis• Lethal dose – 1.4 ml/kg

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NEWER DRUGS

• Varinicline• Rimonabant• Nalmefene• Ondansetron

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VARINICLINE• Nicotinic receptor partial agonist• Association of smoking with alcohol• Acts as a pharmacological antagonist on nicotinic receptors in

presence of full agonist nicotine• Increases dopamine in the mesolimbic pathway reducing the

withdrawal symptoms and craving.• Adverse effects : Neuropsychiatric effects like emotional

lability ,acute psychosis.• FDA warning regarding the use of varinicline in psychiatric

patients.• However preclinical studies have not shown very good result for

alcoholism.49

RIMONABANT

• CB1 receptor inverse agonists• Preclinical studies shown that rats increase

consumption of alcohol on acute and chronic administration of CB1 agonists ,whereas Rimonabant decreases the voluntary intake of alcohol .

• Recently under research for the prevention of nicotine induced relapse to alcohol

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ONDANSETRON

• 5HT3 receptor antagonist• Preclinical studies have shown that

Ondansetron reduces alcohol consumption in rats.

• Suitable for early onset alcoholics responding poorly to psychosocial treatment.(< 10 drinks)

http://www.omicsonline.org/effect-of-full-dose-ondansetron-on-tobacco-use-among-male-alcohol-dependent-outpatients-a-preliminary-study-2155-6105.1000150.pdf

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THANK YOU

Date post:	04-Dec-2014
Category:	Health & Medicine
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Alcohol

Health & Medicine