Alcohol Use Dates Back 7,000 to 10,000 Years Though Scientists Still Debate the Mechanisms of Hangovers Proposed Causes of Hangovers Acute ethanol withdrawal Ethanol can alleviate symptoms Acetaldehyde buildup Acetaldehyde causes similar symptoms as hangovers, though hangovers occur when no acetaldehyde is present Acetate accumulation Acetate levels remain high for several hours after drinking Congeners: other alcohols present in beverages including methanol Pure ethanol can cause hangovers Others debated Dehydration, low blood sugar, electrolyte imbalances, vasodilation, gastric irritation 1
Significant Alcohol Withdrawal Alcohol reduces glutamate activity and increases GABA activity in the brain. Alcohol withdrawal results in opposite effects: Increased glutamate, reduced GABA activity Pharmacotherapy for significant withdrawal: Prevent uncontrolled neural excitation (excitotoxicity) by reducing glutamate activity or increasing GABA activity. Pharmacotherapy for Significant Alcohol Withdrawal Benzodiazepines i for preventing withdrawal seizures Longer half lives than alcohol allow gradual tapering Short term use potential for addiction chlordiazepoxide (Librium ), diazepam (Valium ), lorazepam (Ativan ) 2
Pharmacotherapy for Significant Alcohol Withdrawal Anticonvulsants t Antiepileptic drugs help prevent withdrawal seizures Alternative to benzodiazepines, which have side effects and risks: sedation, psychomotor impairments, abuse potential gabapentin (Neurontin ), pregabalin (Lyrica ), lamotrigine (Lamictal ) Pharmacotherapy for Maintaining Alcohol Abstinence and Relapse Prevention Disulfuram (Antabuse ) Causes averse reaction by inhibiting ALDH resulting in buildup of acetaldehyde Naltrexone (ReVia, Vivitrol depot injection) Opiod antagonist believed reinforcing property of alcohol linked to opiod system Acamprosate (Campral ) GABA agonist, NMDA antagonist (glutamate receptors) FDA approved drugs have limited efficacy Improved efficacy when combined with psychotherapy 3
Inhalants of Abuse Inhalants of Abuse 4
Nitrous Oxide Not to be Confused with Nitric Oxide Nitrous oxide N 2 O Anesthetic, analgesic Nitric oxide NO Cellular signaling molecule vasodilation through relaxation of endothelial smooth muscles Nitric Oxide and Sildenafil Nitric oxide (NO) results in increased cgmp, causing vasodilation. Sildenafil originally studied for hypertension and angina pectoris by inhibiting cgmp degradation. Ineffective for original indication, though noted side effect Vasodilation in the helicene arteries. Where are the helicene arteries? 5
Viagra Sildenafil Stimulation releases nitric oxide (NO) NO activates enzyme guanylate cyclase Viagra, Cialis, and Levitra inhibit degradation of cgmp by blocking PDE5 Nitrous Oxide Historical Recreational Use Early 19 th centuries, nitrous oxide was used recreationally in certain social circles. Laughing gas parties held as early as 1899. 6
Horace Wells Pioneer of Nitrous Oxide Use in Medicine In 1844, the dentist Horace Wells observed Samuel Cooley injure himself under the influence of N 2 O, experiencing no pain nor memory of the injury. First demonstration of nitrous oxide use in surgery December 1844. Other Early Anesthetics 1840s Diethyl ether ( ether ) 1847 Chloroform Neither is in use today for anesthesia. Current applications organic laboratory solvents CH 3 CH 2 OCH 2 CH 3 diethyl ether bp 35 C / mp 116 C CHCl 3 chloroform bp 61 C / mp 64 C 7
Nitrous Oxide Use in Medicine Nitrous oxide is combined with oxygen (O 2 ) for various applications: Oral surgery Childbirth Heart attacks Nitrous Oxide Pharmacokinetics Low solubility in blood and tissues Rapid onset Human metabolism is minimal (<1% metabolized) Rapid clearance via exhalation > room must be well ventilated http://www.medsafe.govt.nz/profs/datasheet/e/entonoxgas.pdf 8
Nitrous Oxide Associated Risks Acute use Hypoxia low oxygen levels. Euphoric effects are not due to oxygen deprivation! Chronic use Vitamin B12 (cobalamine) depletion, leading to neuropathy, anemia Reports of psychiatric disturbances with low B12 levels Vitamin B12 Involved in Brain and Nervous System Functions, Blood Formation and DNA Synthesis 2 3 mcg per day recommended intake Synthesized by bacteria Present mainly in animal derived foods 9
Ideal Gas Law PV = nrt P = pressure V = volume n = number of moles of gas R = ideal gas constant T = temperature If rapidly emptying a nitrous oxide tank, what effect will the pressure drop have on the temperature? Nitrous Oxide Pharmacodynamics Analgesia, anesthesia, and anxiolysis Noncompetitive inhibition of the NMDA glutamate receptor Activation of potassium ion (K+) channels, leading to hyperpolarization 10
Membrane Potential Across Neurons Cells polarized: Outside cell higher [Na+] higher [Cl ] Inside cell higher [K+] higher [A ] (charged proteins) Resting potential 70 mv Ion gradient maintained by active transport (requires energy) Nitrous Oxide Commercially Available for Whipped Cream Canisters Nitric oxide versus other gases N 2 O highly fat soluble and provides 4x volume of whip in whipped cream versus air Air contains 20% oxygen (O 2 ), which oxidizes fats in cream Carbon dioxide (CO 2 ) is acidic when dissolved in water, causing cream to curdle 11