Alcohols And The Pharmacotherapy Of Alcoholism

8/6/2019 Alcohols And The Pharmacotherapy Of Alcoholism

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ALCOHOLS AND PHARMACOTHERAPY OFALCOHOLISM


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INTRODUCTION

x When unqualified, 'alcohol' refers to ethyl

alcohol or ethanol

x Alcohol beverages have been used since

recorded history

x Alcohol is known for intoxication. Rather than as adrug

x Alcohol is the most commonly abused drug in theworld


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x Alcohol abuse: inability to limit alcoholconsumption - becomes a health risk

x Alcoholism: continued consumption of alcohol

in spite of adverse medical or socialconsequences related directly to alcohol

consumption


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Rapidly absorbed from GIT

x Peak levels in 30 min on empty stomach

x Food delays absorptionx Rapid distribution in total body water, tissue

and blood levels almost similar

x Women have higher peak concentrationsx Concentration rises quickly in CNS

PHARMACOKINETICS


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x Over 90% is oxidized in the liver; remainder is

excreted through the lungs and in the urine

x Metabolism follows zero-order kinetics;

independent of time and conc. of the drug

x A typical adult can metabolize 7-10 g/hr


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x During chronic alcohol consumption, MEOS

activity is induced

x Significant in ethanol metabolism and also in

the clearance of other drugsx Increased generation of the toxic byproducts of

cytochrome P450 reactions

x Deficient activity of ALDH -disulifiram like

effects; protective against alcoholism; risk ofsevere liver disease


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PHARMACOLOGICAL ACTIONS

Local actions:x Has mild rubefacient counterirritant andastringent action

x Used as an antiseptic

CNS:

x Alcohol is a neuronal depressant

x Higher areas are most sensitive (primarilyinhibitory) - apparent excitation and euphoria

at lower concentrations

x Gradual CNS depression with increasingconcentrations


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x Alcohol can induce sleep

x Increases pain threshold and also alters

reaction to itx Effects are more marked when the blood

concentration is rising

x Cortex & RAS are most sensitive

x Chronic alcoholism may lead to peripheral

neuropathy, Wernicke-Korsakoff syndrome


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CVS: dose & duration dependent effects

x Smaller doses cause cutaneous and gastric

vasodilatation, BP not affectedx Voderate doses: tachycardia and mild rise in

BP - due to sympathetic stimulation

x Large doses cause fall in BP due to direct

myocardial as well as VMC depression anddirect smooth muscle relaxation

x Chronic alcoholism contributes to hypertension,cardiomyopathy and arrhythmias


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Blood:

x Consumption in moderation increase HDL

x Megaloblastic anemia due to interference of

folate metabolism (diminished hepatic storage)

Respiration:

x Transiently stimulate respiration reflexly

x Directly depress respiratory centre


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GIT:

x Directly and reflexly stimulate gastric secretion

x Higher conc. (>20%) inhibit gastric secretioncause vomiting, mucosal congestion & gastritis

x Lower esophageal sphincter (LES) tone is

reduced - Ted gastroesophageal reflux

x Risk of chronic pancreatitis & stones


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Liver:

x R e d u ce d h e p a t ic g l u co n e o g e ne s i s c a n l e a d

to hypoglycemia ( in acute intoxicat ion)

Chronic a lcohol a b u s e le a d s t o r e v e r sib le

f a t ty l iv e r p r o g r e s s ing t o i r r e ve r s ib le

h e p a ti t is , c i r r h o s is a n d l iv e r f a i lur e


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Body temperature:

x Produce a sense of warmth due to cutaneous

and gastric vasodilatationx Temperature regulating centre depressed at

higher dose

Skeletal muscle:

x Fatigue is allayed by small dosesx Weakness and myopathy in chronic alcoholism


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Endocrine effects:

x Moderate amounts - cause hyperglycaemiax Acute intoxication is associated with

hypoglycaemiax Chronic alcoholism can produce impotence,testicular atrophy, gynaecomastia etc. (altered

Steroid balance)x Reputed as an aphrodisiac

Kidney:

x Can induce diuresis (ADH inhibition)


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Fetal Alcohol Syndrome:

x Chronic maternal alcohol abuse during

pregnancy is associated with teratogenic

effects (leading cause of mental retardation

and congenital malformation)


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Immune System:

x Immune function in some tissues is inhibited

(e.g, the lung), whereas pathologic, hyperactiveimmune function in other tissues is triggered

(e.g, liver, pancreas)

Neoplasia: chronic use increase risk of GI

cancers and also risk of breast cancer


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MECHANISM OF ACTION

x Ethanol affects a large number of membraneproteins

Neurotransmitter receptors

Enzymes

Transporter

and ion channels


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x Enhancement of the action of GABA at GABAAreceptors

x Inhibits the ability of glutamate to open NMDA

receptors

x Action of 5-HT on 5-HT3 inhibitory autoreceptoris augmented

x Can indirectly reduce neurotransmitter release

by inhibiting voltage sensitive neuronal Ca2+channels


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x Blockade of adenosine uptake contribute tosynaptic depression

x Increased turnover of NA, in brain through anopioid receptor dependent mechanism -

important in the pleasurable effects ofalcohol and in the genesis of alcohol

dependence


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x Activity of membrane bound enzymes like

Na+K+ATPase and adenylyl cyclase may be

altered

x The activity and translocation of channel /

enzyme proteins in the membrane could also

be affected


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DRUG INTERACTIONS

x Increases the risk of hepatotoxicity with

acetaminophen

x Additive CNS depression when combined withother CNS depressants

x Disulfiram-like reactions with chlorpropamide,

cefoperazone, cefotetan, moxalactam,

cefamandole, metronidazole, trimethoprim etc.

x Acute alcohol use may inhibit metabolism of

sedative-hypnotics, TCAs, phenothiazines


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ALCOHOL TOLERANCE & DEPENDENCE

x Tolerance - due to changes in the nervous

system (upregulation of pathways) & changes

in metabolic clearance

x Dependence - both psychological & physical

x Physical - responsible for "withdrawal reaction"

x Psychological one is characterized bycompulsive desire to experience rewarding

effects and in current drinkers - desire to avoidnegative effects of withdrawal


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ACUTE ALCOHOL INTOXICATION

Sign and symptoms:

x Vomiting, hypotension, tachycardia, gastritis,

hypoglycaemia, respiratory depression & coma

Treatment:

x Prevent respiratory depression & aspiration of

vomitus

x Add adequate respiratory & CV support


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x Treatment of hypoglycemia and ketosis by

administration of glucose infusion

x Thiamine: 100 mg in 500 ml of glucosesolution infused intravenously

x In case of dehydration and vomiting - give

electrolyte solutions

x Administer potassium and phosphate

depending on the situation


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ALCOHOL WITHDRAWALSYNDROME

x Characterized by motor agitation, anxiety,insomnia; seizure & hallucinations (severe)

Treatment:

x Aim is to prevent seizure, delirium & arrhythmia

x Restore electrolyte balance (K+, mg2+ and

phosphate)x Administer thiamine in all cases


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In severe cases substitute alcohol with BZD

followed by gradually tapering of BZD dose over

several weeks

x Long acting BZD in those with normal liver

function (e.g. chlordiazepoxide/ diazepam)

x Short acting BZD in impaired liver function

(oxazepam/ lorazepam)

x Can be administered orally/ parenterally


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TREATMENT OF ALCOHOLISM

x Started after successful detoxif icat ion

x Drugs are helpfu l in mainta in ing abstinence

and reducing craving (adjunctive therapy)

Naltrexone:

x Long acting opioid receptor antagonist

x Avoid giving with disulf iram - hepatotoxicityx Pat ient should be opioid free

x Dose: 50 mg OD oral ly/ IM inj every 4 wks


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Acamprosate:

x Weak NMDA-receptor antagonist and a GABAA-

receptor activator

x Administered as 1-2 enteric coated tablets

(333 mg) three times a day

x Should not be used in patients with severe

renal dysfunctionx GI adverse effects are important


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DISULFIRAM

Acts by inhibiting "Aldehyde dehydrogenase"

x Flushing, throbbing headache, nausea,

vomiting, sweating, hypotension, and confusion

occur within a few minutes after alcohol

x No effect in non-drinkers

x For full effect 12 hrs are required

x Action persist several days after last dose

x May impair liver function tests

x Adherence to therapy is poor


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METHANOL POISONING & TREATMENT

x Methanol is a CNS depressant

x Toxic effects are largelydue to formic acid

X Blood levels >50mg/di associated with severe

poisoning


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Manifestations of methanol poisoning:

x Vomiting, headache, dyspnoea, bradycardia

and hypotension

x Acidosis is prominent

x Visual disturbances (like being in a snowstorm)

progressing to blindness

x Death is due to respiratory failure


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x Maintain respiration and BP

x Suppression of metabolism by ALD to toxicproducts by ethanol (i.v.) or fomepizole

(15mg/kg iv followed by 10 mg/kg/12hr tillmethanol level falls b e low 2 0 mg/dL)

x Na-bicarbonate infusion to counteract acidosis

x Hemodialysis to enhance removal of methanol

and formate in severe casex Administration of folio acid (Ca-leucovorin 50mg/6 hrly)


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THANK YOU


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Alcohols And The Pharmacotherapy Of Alcoholism