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

The metabolism of alcohol is a very important kinetic. There are two enzyme systems that contribute to the metabolism of alcohol. Acetaldehyde is the end product of both of these systems.

- Alcohol dehydrogenase – this system is activated when low to moderate amounts of alcohol is ingested. Due to the limited amount of NAD co-enzymes, zero order kinetics will be seen which means when these co-enzymes are depletes, the system becomes saturated and the alcohol will not be metabolised, this will or can lead to a build of alcohol (ethanol molecules).

- MEOS – this system is activated to higher concentrations of alcohol present in the blood (>100mg/dL). This activity will increase due to chronic use, thus can lead to tolerance, because patient ingest lots of alcohol, but feel fine due to the rapid metabolism of the MEOS, but this is not good because even if they feel fine at 400mg/dL the body can only handle a certain amount of BAC and thus can lead to instant death if more alcohol is ingested.

Sometimes certain drugs can block the Aldehydedehidrogenase enzyme that breaks acetaldehyde down – this will lead to a hangover effect.

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

Referring to Katzung textbook p. 397. It can be seen that ethanol is metabolised by the two enzyme systems as mentioned above. Where acetaldehyde is the end product. This product is broken down by the enzyme Aldehydedehidrogenase, leading to the formation of actetate that can be excreted by the body.

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

• Disulfiram
• Metronidazole
• Cephalosporine
• Hypopglycemics

This will ensure an acetaldehyde build up that will let the patient feel nauseas or experience a headache. This effects are seen because acetate cannot be formed which will convert to CO₂ and water to be excreted.

It is important to consult a doctor before starting on a herbal drug.

• Ashwagandha (Withania somnifera) – regulates a person’s stress response, can be taken as a tablet or tincture
• Chamomile (herb), used in a tea, extract, tablet or skin cream, it can be used for GAD, some patients may have and allergy to this herb, should not be taken with warfarin and cyclosporine
• Valeriana officinalis –, this is used to manage insomnia, anxiety and depression, available in tea, tablet and tincture. CI in pregnant and lactating women. Has sedative effect NOT TO BE TAKEN WITH BD, BARBS AND DRUGS WITH CNS EFFECTS
• Galphimia glauca – used as a tranquilizer to reduce anxiety, this is a good medicine replacement for GAD, studies show it has a greater effecr than Lorazepam
• Prunus serotina - Wild cherry is mainly used in cough syrup but has a moderate sedative effect.
• Essentials oils such as Lavender are also used as stress reducers. Some even have improved sleep.

• Panax ginseng - CI with insomnia
• Kava-kava - prescribed for anxiety has hepatotoxicity as a side effect, some studies say it is safe, although according to the Katzung textbook it should be avoided

Medicalnewstoday.com. 2020. Herbs for anxiety: 9 calming options. [online] Available at: <https://www.medicalnewstoday.com/articles/herbs-for-anxiety> [Accessed 6 March 2021].

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

In the case of Barbiturates: The more lipid soluble the drug is the easier and faster it will be reabsorbed and redistributed (Thiopentone is an example).

Meaning therapeutic effect will be seen quicker, because lipid soluble drugs redistribute to brain.

Benzodiapines’ lipophilicity is also important for absorption.

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

Highly lipid-soluble drugs given by intravenous or inhalation methods are initially distributed to organs with high blood flow. Later, muscle and fat tissues will take up the drug—plasma concentration falls and the drug is withdrawn from these sites.

Significance is the fact that the drug will be easier absorbed and a quicker therapeutic effect that is reached.

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

BDs are metabolised by hepatic microsomal enzymes. There are three steps namely: Dealkylation, Oxidation and Conjugation

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

Diazepam, Chlorazepate, Prazepam, Chloridiazepoxide and Ketazolam

These active metabolites that are formed can lead to a cumulative effect that can have a toxic effect or an effect for an extended duration.

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

Oxazepam, Lorazepam, Themazepam, Lormetazepam

These drugs are usually the drug of choice in geriatric and neonate patients (they do not have the best liver function), in patients that have liver cirrhosis or patients that already use P450 enzyme inhibitors. Thus all the above mentioned has decreased Cyt P450, so if the drug they take do not need to be broken down by this enzyme it is good, otherwise the drugs will accumulate in the bloodstream and have a toxic effect.

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

Enzyme induction can be defined as the increase in the biosynthesis of catalytically active enzyme following exposure of the organism to chemical agents or physiological conditions.

Therefore: Metabolism increases

- clearance takes place faster

- clearance t½ is shorter.

Enzyme induction will lead to a shorter half live in some benzodiazepines especially Diazepam, this effect is also seen in Carbamazepine and Phenobarbital.

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

Some benzodiazepines have the side effect of anterograde amnesia, which refers to the loss of ability to retain new information, after taking the drug. Thus the drug is found in the patient’s bloodstream.

This is why it is advised not to take BD whilst studying, driving, going to class or doing anything that needs clear cognitive function.

The specific Benzodiazepines that cause this effect are: 

• Alprazolam

• Clonazepam

• Diazepam

• Flunitrazepam

• Lorazepam

• Midazolam,

• Nimetazepam.

• Nitrazepam

• Temazepam,

• Triazolam

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

A patient uses a BD on a long term will see a decrease in the time it takes the patient to fall asleep – thus a patient can use BD to fall asleep easier. patients that already sleep less than six hours a night will see an increase in duration of sleep to about 8 hours, but patients that usually sleep 8 or more hours will not see an effect. BDs have a small decreasing effect and REM sleep; this can explain nightmares or dreams with sudden cessation of the drug.

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

Sedative-hypnotic drugs are used because it promotes anterograde amnesia, which will mean that the patient to do not remember the trauma of a surgery.

Barbiturates (1^st gen anxiolytic sedative-hypnotic drugs) and BD (2^nd gen anxiolytic sedative-hypnotic drugs are usually used.

Midazolam, Diazepam and Lorazepam can be used in combination with Barbiturates in anaesthesia. Thiopental is also used.

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

One of the few clinical indications for barbiturates is Epilepsy, thus will Phenobarbital be used as an anticonvulsant. Certain BDs have anticonvulsant effects and are indicated for status epilepticus: Clonazepam, Lorazepam, Diazepam.

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

Both carbamates and BDs work in on the GABAergic synapse, thus is the effect of GABA potentiated. One of the effects of GABA is a decrease in muscle contractions – thus will it have a muscle relaxing effect.

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

Referring to the ceiling effect. Barbiturates will have a higher risk for respiratory depression in a patient because the benzodiazepine (when it is the only drug) reaches a plateau which means that it will not cause or have risk for respiratory depression.

But BD in combination with other BD can lead to death.

If the levels of these drugs are too high in the patient’s bloodstream it will have an effect on the brain, the brain will then stop some functions, thus will it impact the cardiovascular and respiratory system, there could be trouble breathing or tachycardia. Patient can go into a coma.

FKLG312 SU 1.1

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1. Which types of ion channels are found on the nerve cell membranes?

Voltage-gated channels (examples include Na⁺, K⁺ and Ca²⁺ channels)

Ligand gated channels (has ionotropic and metabotropic receptors) Ligands = neurotransmitters.

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

3. Compare ionotropic and metabotropic receptors.

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

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

- An electrical charge (hyperpolarisation) in the membrane of a postsynaptic neuron caused by the binding of an inhibitory neurotransmitter from a presynaptic cell to a postsynaptic receptor; makes it more difficult for a postsynaptic neuron to generate an action potential.

- An electrical (depolarisation) in the membrane of a postsynaptic neuron caused by the binding of an excitatory neurotransmitter from a presynaptic cell to a postsynaptic receptor; makes it more likely for a postsynaptic neuron to generate an action potential.

6. What is the role of calcium in the development of a synaptic potential

An action potential reaches the axon terminal and depolarization takes place on the membrane, this will lead to the opening of the voltage-gated Ca²⁺ channel, leading to an influx of Ca²⁺ ions. Due to these extra ions the synaptic vesicles releases neurotransmitters. These neurotransmitters will bind to specific receptors.