• How does the sensitivity for blockade by a LA compare regarding the following types of fibres:
  1. myelinated fibres with unmyelinated fibres; and

- myelinated or smaller fibres are easier blocked and unmyelinated or larger fibres are blocked less easier. Fibres in the middle of a thick nerve bundle is blocked slower than those on the outside of the nerve bundle.

(b) pressure/touch nerves with the dorsal nerves that transmit pain impulses?

- When blocking A-type fibres, this influences the proprioception, touch and pressure fibres. These fibres are often the last type to be blocked by local anesthetics and there is thus a decrease in the sensitivity for local anesthetics.

• Make a list of the effects of LA on other tissues.

• In the heart, LA are a class one anti-arrhythmic drug
• In the skeletal muscle, LA have weak blocking action and there is no clinical application.
• What is the basis for the selection of a LA?
• Local anesthetics are normally used for smaller surgical procedures or as a spinal anesthetic. It can also be used as autonomic blockade of ischemic states or post-operative analgesia. When used in low concentrations it can also be used as a slow epidural infusion. Thus they are chosen on the type of procedure that needs to be done.
• They are also chosen on the type of tissue that the local anesthetic must work on and the time that the anesthtic effect needs to be used for.
• Why are LA solutions sometimes saturated with CO₂?
• When it is saturated with CO2, CO2 acts as a buffer which can reduces the pain that the injection can cause, it also helps that there is a faster onset of action for the drug
• Which of the LA are typically used for surface anaesthesia?
• Cocaine
• Benzocaine
• Oxybuprocaine

• Compile a table, listing the major effects on every system (cardiovascular, CNS, renal, hepatic and uterus) for all the inhalation anaesthetics.

• Name the major acute toxic effects of the inhalation drugs.

• Nephrotoxicity
• Hepatotoxicity
• Malignant hyperthermia

Which of the anti-epileptic drugs affect the metabolism of the Pill (oral contraceptive) and what are the implications of this? Which drugs are safe to use in combination with the Pill?

• Phenobarbitone, Phenytoin, Carbamazepine, Oxcarbazepine and Topiramate all decrease the effectiveness of oral contraceptives. The implication of this is that there is a higher dose of the contraceptive needed to give the same effect.
• Drugs that are safe are Valproate, Lamotrigine, Gabapentin, Levetiracetam and Vigabatrin.

Can oral contraceptives also affect the effectivity of the anti-epileptic drugs?

• Yes, drugs like Valproate and Lamotrigine serum levels are decreased by contraceptives.

How does age affect the kinetics of these drugs (from neonates to old age)?

• In neonates we can see that they have a very slow metabolism of medication.
• In babies and children we see that they have a faster metabolism of these drugs than adults.
• In geriatrics we see that they should be given lower dosages because of the fact that there liver and kidney function will not be optimal.

In which cases is plasma blood level monitoring indicated?

• When using drugs like Phenytoin. This is because a small increase in phenytoin can cause a large increase in the plasma level. This is because phenytoin is metabolized with zero order kinetics and there is a constant tempo of biotransformation, irrespective of the concentration of phenytoin that is present.

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

• The MEOS (mixed function oxidases) activity is increased with the chronic use of alcohol. This system can be induced, and is also partially responsible for tolerance when it comes to alcohol intake. When there is chronic use of alcohol, it would also cause there to be more alcohol used to get the same effects, because the receptor undergoes sub-sensitivity.

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

• In the liver it would cause a progressive decrease in liver function, hepatitis and cirrhosis of the liver. This is worse in women than in men. Gluconeogenesis also decreases, hypoglycemia, fat accumulation, nutrient deficiencies all contribute to this. The toxic effects also cause and increase in the activity of liver microsomal enzymes.

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

• Wernicke-Korsakoff syndrome is neurological damage that is normally caused by a thiamine deficiency. It is treated by administration of Thiamine.

Fully explain the foetal alcohol syndrome.

• FAS is when babies are exposed to alcohol during the first trimester or during pregnancy, this causes birth defects in a child. Mental retardation, ADD, perceptual problems , memory and learning disabilities, and psychomotor dysfunction can all be seen in children who suffer from FAS. When the mother drinks alcohol during the pregnancy this causes damage to a child’s neurons and this is what tends to be the cause of these children’s mental and behavioural disabilities.

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

• Acute alcohol use shows a decrease in the metabolism of drugs like, Phenothiazines, TAD’s and other sedative hypnotics.
• Chronic alcohol use increases the metabolic transformation of other drugs like Paracetamol.

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

• TAD’s and sedative hypnotics will supress the CNS further.
• Paracetamol will induce CYP2E1 – which can produce a toxic metabolite.
• Aspirin will have an increase anti-platelet aggregation effects.
• Vasodilators and Hypoglycemic drugs effects are potentiated.

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

• Zero-order kinetics, because alcohol is metabolised by Alcohol dehydrogenase.
• The clinical significance of this is that the alcohol is being metabolised at a constant rate, no matter of the amount of alcohol that is ingested. The reason for this is that there is a limited amount of NAD (a co-enzyme) which means that NAD becomes saturated when there is too much alcohol in the body, which can cause the effects of alcohol to be more easily seen.

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

• 1. The first pathway is by means of alcohol dehydrogenase metabolism. Alcohol dehydrogenase is used for metabolising low to moderate amounts of alcohol. There is a limited amount of NAD, a co-enzyme, which means that this metabolism takes place with zero-order kinetics, an amount of 7-10g is metabolised per hour. The tempo of metabolism is constant.
• 2. The second pathway is by means of MEOS (microsomal ethanol oxidases). This form of metabolism is used with higher concentrations of alcohol (>100mg/dL). This metabolisms activity increases with chronic use of alcohol, metabolism can be induced and is partially responsible for tolerance.
• The end product for both of these metabolisms is acetaldehyde.

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

• Disulfiram.
• Metronidazole.
• Cephalosporins.
• Hypoglycemics.
• The effect of this is that alcohol isn’t converted into acetate from acetaldehyde with alcohol dehydrogenase enzyme. Which can lead to side effects that are normally seen as common hangover symptoms.

Botanical that are used for anxiety include:

• Kava 
• Passion flower
• Valerian
• Chamomile
• Lavender 
• Lemon balm

All of the above-mentioned botanicals have shown to be effective for anxiety but show side effects like nausea, abdominal pain etc.

Botanicals that are used for insomnia include:

• Valerian root
• Chamomile
• Hops
• Lemon balm and passion flower

All of these herbs could also cause side effects like nausea, vomiting, allergic reactions (chamomile) etc and should be considered before use.

Resources:

Bauer, B.A. (2018). Herbal treatment for anxiety: Is it effective? [online] Mayo Clinic. Available at: https://www.mayoclinic.org/diseases-conditions/generalized-anxiety-disorder/expert-answers/herbal-treatment-for-anxiety/faq-20057945 [Accessed 30 Apr. 2021].

WebMD. (2020). Alternative Treatments for Insomnia. [online] Available at: https://www.webmd.com/sleep-disorders/alternative-treatments-for-insomnia [Accessed 30 Apr. 2021].

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

• The tempo of absorption and distribution is influenced by the lipid solubility of the drugs, meaning that a higher lipid solubility would mean faster absorption and distribution.
• The clinical significance of this would be that the rate of absorption and distribution influences the onset of action of a drug.

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

• Redistribution means the distribution or movement of the drugs from the brain to the other organs. This happens with highly lipid soluble drugs are distributed to the brain, heart, kidneys etc and then immediately followed by the muscle and fats.
• The significance of this is that certain drugs can cause a depo effect if it takes too long to be redistributed, this would cause a longer time for elimination to take place etc.

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

• BD’s are metabolized by means of a step by step biotransformation by hepatic microsomal enzymes.
  • Step 1: Dealkylation, this causes the formation of active metabolites
  • Step 2: Oxidation, this step happens in the liver with Cytochrome P450 enzyme which transform the drug into the active metabolite.
  • Step 3: Conjugation, conjugation of the active metabolites with glucuronic acid happens to form the inactive metabolite, which then gets excreted.

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

• Diazepam, Chlorazepate, Prazepam, Chlordiazepoxide and Ketazolam are converted to active metabolites.
• The clinical significance is that when drugs are turned into active metabolites, this extends the drug’s duration of action.

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

• Oxazepam, Lorazepam, Temazepam, and Lormetazepam are not dependant on CYP450 for metabolism.
• The advantages of this is that these drugs can be given to people who have a decrease in CYP450 activity like babies, geriatrics, people with liver cirrhosis etc.

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 when a drug induces the production of an enzyme, which causes increase in the metabolism and liver elimination of the drug.
• Barbiturates are known for this, specifically Phenobarbitone.
• The clinical significance of this would be that there is an increase in some drugs’ elimination and metabolism but this could also cause a decrease in the effectivity of the drug.

Resources:

Brand, L. 2021. Sedative Hypnotic drugs. Study Unit 2[PowerPoint Presentation]. Unpublished lecture notes on eFundi, FKLG 312. Potchefstroom, NWU.

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

• Anterograde amnesia is an inability to remember events occurring during a drug’s duration of action. Drugs that can cause anterograde amnesia are Benzodiazepines.

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

• The effects that sedative hypnotics has on sleep patterns are:
  • Decrease in the time it takes to fall asleep.
  • Increase in a patient’s total sleep duration, for patients who normally sleep less than  hours a night.
  • Benzodiazepines have a small decreasing effect of REM sleep (rapid eye movement), and higher doses of BD’s would decrease the REM sleep of a patient.
  • BD’s also increase the duration of phase 2 NREM sleep (non-rapid eye movement) of a patient and decreases the duration of phase 4 NREM sleep in a patient.
• The significance of these sedative hypnotics to the patient would mean that the patient would get an increase in their sleep if the patient struggles to sleep.

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

• Barbiturates like Thiopentone and BD’s like Midazolam, Diazepam and Lorazepam can be used as supplementary therapy in anaesthesia. Thiopentone can be used as supplementary because of the fact that it is a lipid soluble drug that can cause sedation and can be used as an induction anaesthetic.  The BD’s can be supplementary because they cause CNS suppression and can help patients to fall asleep during procedures.

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

• High dosages of Barbiturates and certain BD’s can be used. Phenobarbitone, clonazepam and clobazam all have selective anticonvulsive effects. BD’s like Diazepam and Lorazepam can be used as an anticonvulsant in patients with status epilepticus.

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

• The mechanism of action is that they inhibit polysynaptic reflexes.

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

• Therapeutic doses of sedative-hypnotics can cause respiratory depression in pulmonary disease and cardiovascular depression in cardiovascular disease. High doses of sedative-hypnotics can cause death due to depression of the medullary respiratory centre.

Resources:

Brand, L. 2021. Sedative Hypnotic drugs. Study Unit 2[PowerPoint Presentation]. Unpublished lecture notes on eFundi, FKLG 312. Potchefstroom, NWU.