alcohol
DESCRIPTION
Alcoholism is a hazard to the society and has a number of medico-legal implications. This presentation is shared with the hope to enlighten the educated masses to abstain from alcohol or consume it in moderate amounts. The impact of alcoholism( acute and chronic) on the human body are so tremendous that it should also serve as a warning for the younger generations as well.TRANSCRIPT
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
1
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.
3
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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CENTRAL NERVOUS SYSTEM
• 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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CENTRAL NERVOUS SYSTEM
• 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
CENTRAL NERVOUS SYSTEM
• 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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CENTRAL NERVOUS SYSTEM
• 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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CENTRAL NERVOUS SYSTEM
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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CARDIOVASCULAR SYSTEM
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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CARDIOVASCULAR SYSTEM
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
CARDIOVASCULAR SYSTEM
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
CARDIOVASCULAR SYSTEM
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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CARDIOVASCULAR SYSTEM
• 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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GASTROINTESTINAL SYSTEM
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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GASTROINTESTINAL SYSTEM
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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GASTROINTESTINAL SYSTEM
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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GASTROINTESTINAL SYSTEM
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
1
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
3
FACTORS AFFECTING ADDICTION
• Agent – Reinforcement of the drug - Cost - Purity - Mode of administration - Rapidity of onset of action
4
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
5
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
6
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
8
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.
12
MODERATION MANAGEMENT
• Here the principle is moderation rather than abstinence.
• Ineffective in dependent individuals• Recommended only in “problem drinkers”
13
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.
21
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
22
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.
24
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
25
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
26
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
30
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
33
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
35
ALCOHOLS AND ITS POISONING
• Four major alcohols that human beings come in contact to are :
-Ethanol- Consumable -Methanol -Ethylene Glycol -Isopropanolol
Non-consumable
36
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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ACUTE METHANOL INTOXICATION
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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ACUTE METHANOL INTOXICATION
• 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
ACUTE METHANOL INTOXICATION
• 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
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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