Module 3

• Benzodiazepines are depressants and can be used in sports to calm the nerves. They have some side affects such as impair the psychomotor coordination and focus at higher doses.
• Sedative hypnotic agents are CNS depressants. The magnitude of its use determines the effects on the CNS.
• As the dosage increases for sedative hypnotic agents, the effects go from anti-anxiety, to sedation, to hypnosis, to general anesthesia. Basically, the person gets more relaxed and tired.
• Most sedative hypnotic agents aim at reducing glutamate firing in the brain, which decreases overall brain activity. This is done by increasing inhibitory signalling in the brain
• Sedative hypnotics use GABA neurons to inhibit glutamate neurotransmitter signalling, resulting in reduced glutamate nerve firing (therefore decreasing excitement and anxiety)
• GABA works in decreasing glutamate by binding to and opening chloride channels, allowing chloride ions to flow into the postsynaptic neuron. The influx of chloride makes it harder for the postsynaptic neuron to transmit incoming messages to other neurons, depressing CNS neuronal signalling
• Benzodazepines are sedative-hypnotics that are usually taken by capsule or tablet, but can be given intravenously. They increase the frequency of chloride channel opening.
• Benzodiazepine therapeutic effects include relaxation, calmness, relief from anxiety or tension. They also produce skeletal muscle relaxation and have anticonvulsant effects.
• Benzodiazepines can result in overdose due to them being the most common drugs in the market, but have a high therapeutic index and are relatively safe, meaning deaths from overdose is rare.
• Flumazenil is an antidote for benzodiazepin in the case of an overdose
• Benzodiazepines short term adverse effects:

  CNS (drowsiness, lethargy, fatigue, impairment of thinking), breathing, motor coordination (such as driving)

  Long term adverse effects:

  Some people might have nothing, and some people might have chronic sedative-hypnotic intoxication, such as impaired thinking, poor judgement, disorientation, etc
• Benzodiazepines can result in birth defects in the fetus of breast feeding or pregnant women. It can also cause cognitive dysfunction in older adults
• Benzodiazepine can result in withdrawal, tolerance, and addiction, but is less likely. Misuse is for recreational purposes, typically in combination with alcohol to enhance CNS depression.
• Barbiturates are sedative hypnotics, and are classified based on their length of action. They are an older class of drugs that have generally been replaced by safer sedative-hypnotic agents.
• Barbituates are administered orally for epilepsy and intravenously for anesthesia. They work by increasing the duration of the opened chloride channels, and demonstrate the full spectrum sedative hypnotics
• Barbiturates therapeutic uses involve tranquility and relaxation, and can induce sleep in high doses. They are rarely used clinically, but can induce anesthesia. They can also be used to stop seizures (anti-epileptic)
• Barbiturates have high a low therapeutic index, and therefore a high lethality rate, hence the reason why it has better alternatives. They also disrupt REM-type sleep.
• Barbiturate short term adverse effects:

  Mild euphoria, dizziness and motor coordination impairment, and depress the cardiovascular system.

  Barbiturate long term adverse effects:

  Chronic inebriation, and impaired memory and thinking.
• Barbiturates potential for misuse is relatively high, equal or greater than alcohol. The pleasurable effects give a significant degree of reinforcement. Postural hypotension is a symptom of withdrawal
• Zopiclone and zolpidem are benzodiazepine-like drugs that bind to a subset of the GABA receptors and cause sedation. They have an advantage over benzodiazepines as they cause less disturbance sleeping patterns (REM sleep). They have more sedative effects than anxiolytic effects.
• Buspirone is an anxiolytic (sedative-hypnotic agent) but acts differently as it touches serotonin receptors instead of GABA receptors. It has an advantage over other sedatives as it does not have additive effects.
• Ethanol is the only drinkable alcohol. It is absorbed 20% by the stomach and 80% by the small intestine. The absorption rate depends on the time to reach the stomach or intestine, and the concentration in the GI tract or presence of food.
• Ethanol distribution is throughout the whole body and brain, and can travel across the placenta into a fetus.
• The metabolism of ethanol is mostly done by the alcohol dehydrogenase enzyme, and is the rate limiting enzyme (depicts speed of the conversion). Other less important pathway is the MEOS (cytochrome P450 system). Acetaldehyde is converted to acetate by the enzyme aldehyde dehydrogenase. Acetate is then converted to water and carbon dioxide by a number of tissues.
• Genetic variability in ethanol metabolism is a thing, and can occur when a variant of the gene that codes for alcohol dehydrogenase (rate limiting). This causes the enzyme to convert alcohol to acetaldehyde very rapidly, which can produce unpleasant side effects such as a flushed face.
• The rate of ethanol metabolism occurs at a constant rate, irrespective of blood concentration. This is due to alcohol dehydrogenase being rate limiting at 20 mg/100 mL of blood. This means metabolism is about 120 mg ethanol/kg body weight /hour
• 95% of Ethanol is excreted by the liver through biotransformation. 5% is excreted in the breath, urine and sweat.
• Ethanol is used clinically to treat fever through sponges, as a skin disinfectant, antidote in the treatment of methanol poisoning, and as a hand sanitizer.
• Ethanol is considered a CNS depressant, and the effects are proportional to blood alcohol concentration. 50-100 BAC results in sedation, 100-200 BAC results in impaired motor function, 200-300 BAC results in emesis and stupor, 300-400 BAC results in a coma, and more than 400 results in respiratory depression and death.
• Having a BAC of 0.05% is a provincial offence, and having a BAC of 0.08% is a criminal offence. Before the age of 22, any above 0% is illegal
• Alcohol works by binding to the chloride ion channel and augmenting GABA mediated neuronal inhibition. It is a different binding site than sedative-hypnotic agents as it binds on the alpha area and not the gama area.
• Low dose effects of alcohol use:

  Cardiovascular: vasodilation - flushing of vessels to the skin (1-3 drinks) and depress the cardiovascular system (>5 drinks)

  Stomach: increased gastric secretion (1-3 drinks) and gastritis (irritation of the inner lining of the stomach)(>5 drinks)

  Liver: Has no effects (1-3 drinks) and hypoglycemia (low blood sugar) from acute high doses of of alcohol.
• Short term adverse effects of alcohol:

  memory loss, psychiatric effects (depression, over-sedation), overdose (happens with excessive alcohol drinking)

  Long term adverse effects of alcohol:

  CNS (mental disorders, such as dementia, thinking, and judgement), cardiovascular (cardiomyopathy, stroke), liver (alcoholic liver disease)
• Fetal Alcohol Spectrum Disorder is a disorder from chronic alcohol use that affects the fetus when pregnant. A safe dose of ethanol in pregnancy is not established, therefore it should be fully avoided.
• Alcohol use during drug therapy can result in an additive synergistic effect of CNS depression (if consumed with CNS depressants) and inhibition of metabolism of certain drugs, like sedative-hypnotics
• Chronic alcohol use before drug therapy can result in drug-drug interactions such as increasing the activity of metabolizing enzymes in the liver, resulting in increased metabolism of certain drugs (only occurs if there is no co-existing ethanol-induced liver injury
• Alcohol produces both reinforcing and sedating effects in the CNS, which contributes to its potential for misuse and SUD. Misuse potential is moderate, tolerance is possible, and cross-tolerance with other drugs occurs with other depressants such as hypnotics and anesthetics.
• Alcohol withdrawal can be treated by balancing electrolytes and fluid, and to prevent seizures. More severe withdrawal can be treated with diazepam (a benzodiazepine)
• Alcohol-deterrent or alcohol-sensitizing drugs, such as Naltroxene, treats alcohol addiction. It diminishes the craving for ethanol by blocking the dopaminergic reward pathways in the brain.
• Cannabis sativa is a plant that contains 60 chemical compounds. THC is the most potent and accounts for most psychoactive effects