Alcohol & Drug Abuse : The Downward Spiral

Alcohol Alcoholism is a complex disorder with genetic and environmental determinants. Women have higher plasma level than men for equivalent dose – first pass metabolism and body water. The majority is oxidized, primarily in the liver; breath contains 0.05% of blood.

Alcohol Content in Drinks Beer: 4% alcohol X 12 oz =.48 oz alcohol Wine: 12% alcohol X 4 oz =.48 oz alcohol Whiskey: 40% alcohol X 1.25 oz =.5 oz alcohol All three have almost the same alcohol content about 14 g despite different volumes. The typical adult can metabolize 7–10 g (150–220 mmol) of alcohol per hour, or approximately 120 mg/kg per hour.

Alcohol concentration-Effect BAC [mg%] Effects in non-tolerant individuals Mood elevation. Slight muscle relaxation and slow reaction time Increased reaction time, decreased fine muscle coordination, ataxia and slurred speech Emesis and stupor Coma Severely intoxicated. Respiratory depression and death

Ethanol Alcohol Dehydrogenase Pathway in Liver  The major pathway of alcohol metabolism converts alcohol into acetaldehyde and leads to generation of NADH.  The rate of ethanol oxidation is determined by the capacity to re-oxidize NADH.  If the ability of the liver to maintain redox homeostasis is overwhelmed, then a number of metabolic disturbances arise including lactic acidosis, ↑ uric acid and abnormalities of lipid metabolism.

Ethanol Very less and upto10% in chronic alcoholism

Neuropharmacology: Alcohol Effects on GABA system – Interaction with GABA-A receptor and facilitation of GABA transmission Sedative and anxiolytic effects Effects on NMDA Glutamate system – Blockage of NMDA receptor Sedative/hypnotic effects "Blackouts"—periods of memory loss that occur with high levels of alcohol— may result from inhibition of NMDA receptor activation. Effects on Dopamine system – Increase dopamine in mesocorticolimbic system Reinforcing, rewarding effects Effects on opioid system – Increased release of endorphins and interaction with mu receptors Pleasure and reward.

Alcohol as a Reinforcer: Neural Systems Activation of mesocorticolimbic system

Ethanol Toxicity of Ethanol: Acetaldehyde acts as a poison by inhibiting oxidative phosphorylation. Lactic acidosis. Hypoglycemia. All redox reactions are perturbed Death can occur when the blood alcohol levels is > mg/dl.

Alcohol withdrawal syndrome Withdrawal syndrome of alcohol Tremors, hallucinations, seizures, insomnia, hyperthermia, nausea/vomiting Delirium tremens or withdrawal syndrome is treated by chlordiazepoxide or diazepam.

Ethanol Disulfiram : Acts by inhibiting aldehyde dehydrogenase and thus acetaldehyde is accumulated. It should not administered with alcohol. It results in flushing, headache, tachycardia, vomiting, confusion and convulsions. Naltrexone helps to abstain from alcoholism by decreasing craving and relapse. Drugs causing disulfiram like effect: Metronidazole, Cefotetan, Chlorpropamide

Ethanol Drugs used to treat alcohol dependence To render alcohol unpleasant -Disulfiram To reduce alcohol craving a.Acamprosate – NMDA antagonist b.Naltrexone – Opioids Antagonist

Methanol  Methyl alcohol ‘Wood alcohol’ is widely used in the industrial production of organic solvents (windshield washing products).  The most characteristic feature methanol poisoning is an initial acidosis followed by a delayed visual disturbance due to formic acid induced injury to ganglionic cells of retina with potential blindness.

Methanol The treatment of methanol poisoning includes – 1.Suppression of metabolism by alcohol dehydrogenase – Ethanol and Fomipezole  Fomipezole (antizol) is an alcohol dehydrogenase inhibitor, approved for the treatment of methanol and ethylene glycol poisoning.  Ethanol is also used for treatment of poisoning by : Methanol, Ethylene glycol by competitive inhibition of alcohol dehydrogenase (ADH)  Methanol concentration in excess of 50 mg/dl is an absolute indication for hemodialysis.

Ethylene glycol  Ethylene glycol is widely used as an automotive antifreeze, engine coolants and hydraulic brake fluids..  Ethylene glycol is toxic, and its ingestion should be considered a medical emergency. Fomipezole Renal failure Ca Oxalate stones

Fetal Alcohol Syndrome (FAS) Most common preventable cause of adverse CNS development 4,000-12,000 infants per year in US Characteristics Growth retardation Cranio-facial malformations CNS dysfunction

Drugs of abuse Abuse of a drug is construed as any use of a drug for non-medical purposes, usually for altering consciousness and/or body building. Positive reinforcement property of a substance is used for the assessment of abuse potential. Chronic use of a drug over a long period produce a state of tolerance. Tolerance signifies a decreased response to the effects of a drug, necessitating even larger doses to achieve the same effect. The degree of tolerance is proportional to the dose and duration of the drug use.

Drugs of abuse Psychological dependence is manifested by compulsive drug seeking behavior for personal satisfaction, often in the face of known risk to health. Deprivation of the agent results in craving. Physical dependence – A physiological state of adaptation characterized by the tolerance to the drug effects and emergence of a withdrawal syndrome during prolonged abstinence.

The Pleasure Reward Pathways includes the dopaminergic pathway from the ventral tegmental area (VTA) to the nucleus accumbens (NA) and extending to the prefrontal cortex.

Nicotine and Alcohol  Women older than 30, who smoke and also take oral contraceptives are more prone to cardiovascular diseases than others.  Nicotine chewing gum is approved by the FDA for the treatment of nicotine dependence.  Another approach to smoking cessation is the nicotine transdermal skin patch.  Bupropion (Zyban) is used to reduce the craving.  Varenicline (chantix) is a nicotinic receptor partial agonist.

 Cocaine cause vasoconstriction, dilated pupils and ↑temperature.  Toxic psychosis due to cocaine is characterized by auditory and tactile hallucinations.  Cocaine-related deaths are often of cardiac arrest or seizures. COCAINE

MDMA  MDMA (Ecstasy) is a synthetic, psychoactive drug similar to methamphetamine.  The primary effects of MDMA includes warmth, feelings of openness, euphoria and empathy.  MDMA can interfere with the ability to regulate temperature. This can lead to hyperthermia resulting in kidney and cardiovascular failure.

MDMA MDMA (green) fools the cell into dumping lots of serotonin/dopamine (red) into the synapse, causing a surge of exhilaration. Chronic MDMA exposure damage serotonin neurons leading to symptoms of depression

Flunitrazepam  Flunitrazepam (Rohypnol) is a powerful hypnotic drug.  It can incapacitate victims and prevent them from resisting sexual assault when mixed with alcohol.  It can produce “anterograde amnesia” and may be lethal.  Anti-dote is flumazenil

Phencyclidine  PCP is a popular hallucinogen.  PCP acts by blocking NMDA receptors  It alters mood in unpredictable fashion, individuals can become animated, acts of self- injury like suicide, and attacks on others or destruction of property may be seen. It can also can induce psychotic reactions.  Overdose of PCP includes dilated pupils, nystagmus, hypertension.  Chronic use can cause memory loss, difficulties with speech and thinking, and they persist even after stopping PCP.

Lysergic acid diethylamide  LSD is a potent hallucinogen which activates 5-HT receptors in the neocortex, limbic system and brain stem.  LSD produces delusions, visual, auditory and olfactory hallucinations.  Sensations may seem to "cross over" giving the feeling of hearing colors and seeing sounds (synesthesia). These changes can be frightening and can cause panic.  These adverse experiences with LSD are referred as a "bad trip."