1. What are the possible mechanisms involved in the occurrence of tolerance to chronic alcohol intake?

• Central nervous system adaptation of receptor or second messengers
• Increase in the rate of metabolism
• The enzyme system MEOS (mixed function oxidases) is also partially responsible for tolerance. 

2. What are the toxic effects of chronic alcohol consumption on the liver and hepatic metabolism?

Chronic alcohol consumption has the following effects on the liver and hepatic metabolism - 

• Hepatitis
• Liver cirrhosis
• Decrease in liver function
• Decreased gluconeogenesis
• Hypoglycaemia 
• There is progressive reduction in liver function, hepatitis and cirrhosis
• Increase in the activity of liver microsomal enzymes

3. What is Wernicke-Korsakoff-syndrome and how is it treated?

Wernicke-Korsakoff syndrome (WKS) is a type of brain disorder caused by a lack of vitamin B-1, or thiamine. It includes symptoms like confusion and loss of mental activity that can progress to coma and death, ataxia that can cause leg tremor, vision changes such as abnormal eye movements, double vision and eyelid drooping. 

This syndrome is treated by injecting Thiamine intravenously because abdominal absorption of thiamine is hampered in affected individuals.

4. Fully explain the fetal alcohol syndrome.

Fetal alcohol syndrome is a condition in a child that results from alcohol exposure during the mother's pregnancy. Fetal alcohol syndrome causes brain damage and growth problems. The problems caused by fetal alcohol syndrome vary from child to child, but defects caused by fetal alcohol syndrome are not reversible.  Some of these symptoms occurs - mental retardation, growth deficiency, smaller brain, characteristics under development of middle facial area.

5. How do the pharmacokinetic interactions of acute alcohol consumption differ from that of chronic alcohol consumption?

Acute alcohol consumption decreases the metabolism of drugs. This causes the drug to build up in the body and accumulative central nervous system suppression is a result. Examples of these drugs include: Phenothiazines, tricyclic anti-depressants and other sedative-hypnotics.

Chronic consumption of alcohol increases the metabolic transformation of other drugs. This causes a shortened effect of the drug.

6. Name 4 drug interactions with alcohol where the pharmacological effects of the other drugs are potentiated by alcohol.

• Vasodilators
• Hypoglycaemic drugs
• Aspirin
• Paracetamol

1. What type of kinetics applies for alcohol in the body? Also, explain the clinical significance of this.

At a specific level of ethanol achieved in blood, the rate of oxidation follows zero-order kinetics. The typical adult can metabolize 7–10 g (150–220 mmol) of alcohol per hour. After ingestion of alcohol in the fasting state, peak blood alcohol concentrations are reached within 30 minutes. The presence of food in the stomach delays absorption by slowing gastric emptying. Distribution is rapid, with tissue levels approximating the concentration in blood. The volume of distribution for ethanol approximates total body water (0.5–0.7 L/kg). After an equivalent oral dose of alcohol, women have a higher peak concentration than men, in part because women have a lower total body water content and in part because of differences in first-pass metabolism. In the central nervous system (CNS), the concentration of ethanol rises quickly, since the brain receives a large proportion of total blood flow and ethanol readily crosses biologic membranes.

2. Give a brief summary of the metabolic pathways of ethanol metabolism.

There are 2 enzyme systems that metabolize ethanol to acetaldehyde:

• Alcohol dehydrogenase (ADH):

The NAD+, found mainly in the liver and gut, accounts for the metabolism of low to moderate doses of ethanol. Because of the limited supply of the co-enzyme NAD+, the reaction has zero-order kinetics, resulting in a fixed capacity for ethanol metabolism of 7-10g/h. Gastrointestinal metabolism of ethanol is lower in women than in men. Genetic variation in this system, affects the rate of ethanol metabolism.

• Microsomal ethanol-oxidizing system (MEOS):

At blood ethanol levels of 100 mg/L or higher, the liver microsomal mixed function oxidase system that catalyses most phase 1 drug-metabolizing reactions, contributes to ethanol metabolism. Chronic alcohol consumption induces CYT P450 enzyme synthesis and MEOS activity; this is partially responsible to the development of tolerance to ethanol. The primary isoform of CYT P450 induced by ethanol-2E1, converts acetaminophen to a hepatotoxic metabolite.

3. Which drugs can affect this metabolism and what are the effects thereof?

Disulfiram, Metronidazole, Cephalosporins and Hypoglycemic drugs inhibit aldehyde dehydrogenase so that acetaldehyde remains unchanged in the bloodstream. Side effects of sufficient acetaldehyde in the bloodstream include nausea & vomiting, headache, burning and general malaise.

For quite a number of preparations of herbal/natural origin in pharmacies or shops, claims are made that they have anxiolytic and/or sedative-hypnotic properties. Your textbook (Katz) discusses a number of these preparations in Chapter 64. Use that information together with a search on the internet and compile a brief report on the use of these alternative medicines in the treatment of anxiety and insomnia. 

There are a number of herbal and natural products available in pharmacies which states that it can help with the treatment of Insomnia and Anxiety. These herbal and natural supplements have been used long before chemical medication, and they do have beneficial value.

Herbal and natural products that helps with insomnia:

Valerian root. Some studies have suggested that the root of valerian (Valeriana officinalis) may help with the onset of sleep and with sleep maintenance. However, more research is needed before a final conclusion can be made about the safety and effectiveness of valerian for insomnia. It's possible that it can interfere with some medications. It also has side effects and is not safe in small children or during pregnancy.

Chamomile. Chamomile is another commonly used herb for the treatment of insomnia. More research is needed, however, to see if it is effective. The FDA considers chamomile to be safe and the herb has no known adverse effects. You should not take it, though, if you are sensitive to ragweed or chrysanthemums or other members of the Compositae family such as daisies or sunflowers. You could develop contact allergies if you are. 

Other herbs promoted as effective sleep remedies include green tea (which contains L-theanine), Jin Bu Huan (Chinese herb) and St. John’s Wort (Hypericum perforatum). These still need to be studied to determine their safety and effectiveness.

Herbal and natural products that helps with anxiety:

Kava. Kava appeared to be a promising treatment for anxiety, but reports of serious liver damage.

Passion flower. A few small clinical trials suggest that passion flower might help with anxiety. In many commercial products, passion flower is combined with other herbs, making it difficult to distinguish the unique qualities of each herb. Passion flower is generally considered safe when taken as directed, but some studies found it can cause drowsiness, dizziness and confusion.

Valerian. In some studies, people who used valerian reported less anxiety and stress. In other studies, people reported no benefit. It can cause some side effects such as headaches, dizziness and drowsiness.

Chamomile. Limited data shows that short-term use of chamomile is generally considered safe and can be effective in reducing symptoms of anxiety. But chamomile can increase the risk of bleeding when used with blood-thinning drugs. Use of chamomile can cause allergic reactions in some people who are sensitive to the family of plants that includes chamomile. Other members of this family are ragweed, marigolds, daisies and chrysanthemums.

Lavender. Some evidence suggests that oral lavender or aromatherapy with lavender can reduce anxiety; however, evidence is preliminary and limited. Oral lavender can cause constipation and headaches. It can also increase appetite, increase the sedative effect of other medications and supplements, and cause low blood pressure.

Lemon balm. Preliminary research shows lemon balm can reduce some symptoms of anxiety, such as nervousness and excitability. Lemon balm is generally well-tolerated and considered safe for short-term use, but can cause nausea and abdominal pain.

• What factors may affect the absorption and distribution of sedative-hypnotic drugs? What is the clinical significance thereof?

The rate of absorption and distribution is determined by the fat solubility of the drugs. Therefore the higher the lipid solubility, the faster the drug will reach the break.

The clinical significance will therefore be the starting time of the specific drug, because the faster a drug is absorbed and distributed, the faster it will start working and exert effects.

• What is meant by redistribution and what is the significance thereof?

Redistribution is when a drug moves from its original place of action to other tissue and there an accumulation occurs, it forms a storage site and results in the medication being administered to the body for a longer period of time. It is important to take this into account when administering the drugs as they can cause several unwanted effects.

The importance of this is that when the drug has moved from the brain to other tissues, such as the adipose tissue, it can cause a depot that ultimately affects the rate of release of the drug. The altered rate of release will eventually also have an effect on the rate at which the drugs are eliminated from the body.

• How are the BDs metabolized? Name the various steps in the process.

Benzodiazepines are biotransformed by liver microsomal enzymes under normal conditions in these three steps.

1 - Dealkylation (The process gives rise to the formation of active metabolites)

2 - Oxidation (The process takes place in the liver and the enzyme Sit. P450 converts the drug to active metabolites)

3 - Conjugation (Phase two where the active metabolites are metabolised with Glucuronic acid to form an inactive metabolite)

• Which BDs are converted to active metabolites? What is the significance thereof?

Diazepam, Chlorazepate, Prazepam, Chlorodiazepoxide, Ketazolam.

The importance of this is therefore that the active metabolites that are formed prolong the duration of action of the drugs.

• Which BDs are not dependent on the cytochrome P450 oxidative enzymes for metabolism? What are the advantages thereof?

Oksazepam, Lorazepam, Temazepam, Lormetazepam. 
Advantages of these drugs, they are considered as selectives which have reduced cytochrome P450 activity so that metabolism can still take place adequately. For example, in the elderly ,in neonates and even people with liver cirrhosis the Sit. P450 activity decreases.

• What is enzyme induction? Which of the sedative hypnotic drugs are known for this?. What is the clinical significance of enzyme induction?

Enzyme induction is an increase in the biosynthesis of the catalyzing enzyme. Examples include cimetidine, ketoconazole, erythromycin, fluvoxamine. THe mportance of enzyme induction is that it can accelerate the breakdown of drugs that can be important in toxicization. 

• What does anterograde amnesia mean and which drugs can cause this effect?

Anterograde amnesia is the inability to remember the memories and happenings during the time of use of a drug, leading to a partial or complete inability to recall the recent past. This disorder is  usually caused by benzodiazepine drugs such as midazolam, lorazepam and diazepam. 

• Name the effects of the sedative-hypnotic drugs on the normal sleep pattern and explain their significance to the patient.

Benzodiazepines reduce the time to fall asleep and increase the total sleep time. It increases the duration of phase 2 Non rapid eye movement (NREM) sleep and Benzodiazepines also have a small reducing effect on Rapid eye movement (REM) sleep. 

High doses of BD's reduce REM sleep and Benzodiazepines reduce the duration of phase 4 NREM. Tolerance effects can occur on sleep patterns after 1-2 weeks of using hypnotics. Gradual withdrawal is recommended so that side effects such as nightmares and relapsing insomnia can be avoided.

Short-acting BDs is used in patients who have difficulty falling asleep, such as Midasolam or Triasolam

Intermediate BDs is used in patients who wake up early in the morning. 

Long-acting BDs helps the control of anxiety.

• Which of the sedative-hypnotic drugs are used as a supplementary therapy in anaesthesia?  Can you explain why?

Barbiturates and Benzodiazepines such as Midazolam, Diazepam and Lorazepam.

These drugs are used as adjunctive therapy in anesthesia, because they often cause anterograde amnesia. That is, if a patient were to wake up, during or after an operation, the patient would not remember the events.

• Which of the sedative-hypnotic drugs are used as anticonvulsants?

Phenobarbitone coupled with a benzodiazepine, thiopentone, nitrazepam, clobazam, clonazepam.

• What is the mechanism of the muscle-relaxing effects of some of the carbamates and the BDs?

Muscle-relaxing effects occur because the drugs inhibit the polysynaptic reflexes.

• Discuss the effects of the sedative-hypnotic drugs on the respiratory and cardiovascular systems.

Sedative-hypnotic drugs cause respiratory depression in a person who has a pulmonary disease and can also cause cardiovascular suppression in a patient who has a cardiovascular disease. Therefore, this effect should be considered especially in the case of intravenous administration because the effects may then be more dangerous. 

• What type of ion channels are found on nerve cell membranes?

Voltage-gated ion channels

Ligand-gated ion channels

• Name 3 differences between voltage-gated and ligand-gated ion channels.

• Compare ionotropic and metabotropic receptors.

Ionotropic :

- Directly bind to the receptor to open ion channels. 

- Responsible for opening of ion channels.

- Activation lasts for milliseconds.

Metabotropic :

- Does not bind to receptor, but is involves the use of 7-transmembrane G-protein receptors, that releases secondary messengers to therefore open the ion channels.

- Responsible for metabolic changes.

- Activation lasts from seconds to minutes.

• Classify the CNS receptors into ionotropic and metabotropic and know the transduction mechanism of each receptor.

Ionotropic : 

- GABAᴀ

- Nicotinic (Acetyl choline)

- EAA (Glutamate)

- Serotonin (5-HT₃)

Metabotropic : 

Has two transduction systems namely; the Adenyl cyclase system and the Phospholipase system.

Adenyl cyclase system :

- Beta (β₁₊₂)

- Dopamine (D₁₊₂)

- Alpha (α₂)

- Serotonin (5-HT_1A+B)

- Cholineergic Muscarine (M₂)

Phospholipase system :

- Alpha (α₁₎

- Serotonin (5-HT₂₎

- Cholineergic Muscarine (M₁)

- Histamine (H₁)

• Explain the difference between an EPSP and an IPSP and give examples of each.

EPSP : Excitatory Post Synaptic Potential, is the change in membrane voltage of a postsynaptic cell following the influx of positively charged ions into a cell as a result of the activation of ligand-sensitive channels.

EPSP Example : Na⁺ 

IPSP : Inhibitory Post Synaptic Potential, is an electrical charge in the membrane of a postsynaptic neuron caused by the binding of an inhibitory neurotransmitter from a presynaptic cell to a postsynaptic receptor. It makes it more difficult for a postsynaptic neuron to generate an action potential.

IPSP example : Cl^-

• What is the role of calcium in the development of a synaptic potential?

Calcium ions entering the cell through voltage gated ions causes and action potential which stimulates the axon terminal to release neurotransmitters, which then creates a synaptic potential. Therefore, calcium is important in the formation of neurotransmitters.