Name an example of each of the three phenothiazine sub-families and state how they differ from one another in terms of potency and side effects.

Aliphatic side chain – Chlorpromazine

Piperidine side chain – thioridazine 

Piperazine side chain – Perphenazine 

Aliphatic & piperidine compounds – Low potency, little EPS, severe sedation, strong anti-cholinergic effects, strong alpha-lytic effects and are cardiotoxic. 

Piperazine compounds – Higher potency, more EPS, less sedation, weaker alpha-lytic effects, weaker anti-cholinergic effects and less cardiovascular side effects. 

Which receptors in particular are blocked by the typical antipsychotic drugs?

Typical antipsychotic drugs block the mesolimbic D2 receptors.

How does the mechanism of action of the atypical drugs differ from that of the typical drugs?

Atypical drugs block the 5-HT2a receptors MORE than the D2 receptors. 

Which of the receptors blocked by the older drugs reduce the risk of extrapyramidal side effects?

The low affinity for blockade of D2 receptors reduces the risk of extra-pyramidal side effects. 

Which of the older drugs have a high incidence of extrapyramidal side effects? What is the reason for this?

Piperazine compounds, because they have a high potency and a high affinity for D2 receptors. 

Because of which receptor(s) blockade do the aliphatic group of drugs have a high incidence of autonomic side effects?

Muscarinic receptor blockade 

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? 

Phenytoin, phenobarbitone and carbamazepine decrease the Pill’s effectivity and therefore the chance of unplanned pregnancy is greater.

Drugs that work with the pill:

• Valproate 
• Lamotrigine

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

Oral contraceptives decreases Lamotrigine and Valproate’s plasma levels, and therefore these drugs dosages would have to be increased to keep them from becoming sub-therapeutic while taking the pill. 

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

• Neonates have slower metabolism because they have reduced hepatic activity and therefore the drugs will stay in their systems for longer.
• Babies and children have faster metabolism than in adults and they might require a higher dose than an adult.
• Geriatrics need to be given lower dosages due to their lowered metabolic activity. 

In which cases is plasma blood level monitoring indicated?

• Valproate decreases the metabolism of Lamotrigine, and this can lead to toxicity. Therefore, blood levels should be monitored.  

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

Tolerance to alcohol might result from ethanol-induced up-regulation of the MEOS pathway in response to continuous presence of ethanol in the system. This means that more alcohol is metabolized per unit time, which results in a higher tolerance. 

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

Alcohol abuse causes progressive liver function decline. This can lead to alcoholic hepatitis, liver cirrhosis and liver failure. Gluconeogenesis decreases which leads to hypoglycaemia. There is dysregulation of Fatty Acid oxidation and synthesis which leads to fat accumulation. 

The MEOS system is also upregulated which results in increased metabolism of other drugs. 

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

Wernicke-Korsakoff syndrome is an uncommon syndrome characterized by neurological damage, ataxia, paralysis of the facial muscles, confused state that can develop to coma/death. 

This syndrome is associated with Thiamine deficiency and therefore can be treated with parenteral Thiamine.  

Fully explain the foetal alcohol syndrome.

Foetal alcohol syndrome is the result of chronic maternal alcohol abuse during the 1^st trimester of pregnancy. Alcohol is associated with teratogenic effects, and crosses the placenta, to reach concentrations in the fetus that are similar to those in the mother. Since the fetus’ liver has little to no alcohol dehydrogenase enzymes, it relies on the mother and placental enzymes for elimination of alcohol. 

Children that are exposed to ethanol while in utero may have a wide range of developmental disabilities, cognitive and behavioural deficits that stem from damage to developing neurons. 

Developmental disabilities include: mental retardation, attention deficit disorders, perceptual problems, memory and learning disabilities, and psychomotor dysfunction. 

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

Chronic alcohol abuse increases the metabolism of drugs, while acute alcohol abuse decreases the metabolism of drugs. 

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

• paracetamol,
• aspirin,
• vasodilators,
• Benzodiazepines

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

Ethanol gets eliminated from the body through zero-order kinetics. This means that no matter what the BAC is, and even when the amount of alcohol intake increases, the elimination rate stays the same. 

This means that if a person drinks a lot of alcohol rapidly, the ethanol will accumulate in the body and exaggerate the effects thereof. 

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

Alcohol is metabolized mostly in the liver by 2 pathways/systems, namely Alcohol dehydrogenase system and Microsomal Ethanol-Oxidizing system. 

Alcohol dehydrogenase: is used when there is low to moderate amounts of ethanol in a person’s blood. Alcohol dehydrogenases convert the ethanol to acetaldehyde by means of the NAD+ coenzyme. There are limited NAD+ enzymes and they may become saturated. 

Acetaldehyde is a highly toxic substance and known carcinogen, which is further metabolized into a less active metabolite, acetate.

Microsomal Ethanol-Oxidizing system (MEOS): is used when there are higher concentrations of ethanol in a person’s blood. Here, mixed function oxidases convert ethanol into acetaldehyde when it binds to the binding site of CYP2E1. The acetaldehyde is then converted to acetate. This system only kicks in when a person has had large amounts of alcohol and is increased with the chronic use of alcohol and increases a person’s tolerance to ethanol.

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

• Disulfiram
• Metronidazole
• Cephalosporins
• Hypoglycaemics 

These drugs block the effects of acetaldehyde dehydrogenase which results in the accumulation of acetaldehyde, causing an unpleasant reaction. These reactions include:

• facial flushing,
• nausea,
• vomiting,
• dizziness, 
• headaches, etc. 

These drugs are used to deter alcoholics from drinking.  

Using natural herbs and botanicals should be considered to treat patients as many of the western anxiolytic and sedative-hypnotic drugs available can have unpleasant adverse effects and have the potential to form dependence. 

However, herbal medication can still have adverse effects and interactions with other medications so this should be kept in mind.

Herbal remedies for treating anxiety:

• Ashwagandha
• Chamomile
• Valerian root
• Lavender
• Passionflower
• Kava kava
• Canabidiol  

Herbal remedies for treating insomnia:

• Valerian root
• Chamomile
• Passionflower
• Hops
• St. Johns Wort 

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

Lipophilicity plays a major role in the absorption and distribution of sedative-hypnotic drugs. The more lipophilic the drug is, the quicker it is absorbed into the CNS and the faster it spreads throughout the CNS. Thus, the drug will have a rapid onset of action when it is lipophilic. 

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

Redistribution occurs when drugs have a high lipophilicity. These drugs are fat soluble and therefore spread to surrounding tissues,  usually fatty tissues, where it causes a depot effect resulting in the slow release of the drug. 

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

Benzodiazepines are metabolised by hepatic microsomal enzymes in three steps.

Step 1: Dealkylation (can form active metabolites)

Step 2: Microsomal oxidation (Phase 1 reactions, catalysed by cytochrome P450 enzymes especially CYP3A4, active metabolites can also be formed here)

Step 3: Conjugation (Phase 2 reactions where the oxidised metabolites conjugate with endogenous substances in the body, usually glucuronic acid, to form an inactive metabolite which is excreted in the urine.) 

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

Diazepam, Chlorazepate, Prazepam, Chlordiazepoxide and Ketazolam are all converted to active metabolites. These drugs have prolonged action, and should therefore be used with caution when given to older people, neonates or people on CYP450 inhibitor drugs. 

These patient’s liver function could be reduced and with the already prolonged action, the break down would be slowed as well and the metabolites will build-up.

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 dependent on the cytochrome P450 enzymes. Therefore they are the drug of choice for people who have reduced CYP450 activity. This includes the elderly, neonates or people on CYP450 inhibitor drugs. 

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 the action of the enzymes is promoted. This means that the enzyme will metabolize the drugs much quicker into inactive metabolites. Enzyme induction will reduce the duration of action of these drugs.

Sedative-hypnotic drugs that are known for this include Phenobarbital and Meprobamate. 

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

Anterograde amnesia is when a patient is not able to remember things that have happened while a specific drug is in their system. Therefore, it is memory loss during the drugs action.

Drugs which can cause this effect are benzodiazepines such as midazolam, flunitrazepam, lorazepam, temazepam, etc. 

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

These drugs decrease the time that it takes for the patient to fall asleep, and increases the amount of sleep duration (if the patient originally only slept for <6 hours). The duration spent in stage 2NREM sleep is increased, but the duration spent in REM is decreased. 

The effects caused by the drug are helpful to the patient to treat insomnia. With a better sleep cycle, the patient will have a better mood and therefore quality of life will increase. 

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

Benzodiazepines such as Diazepam, Lorazapam and Midazolam are used supplementary IV in aneasthesia. These drugs cause anterograde amnesia, and they help the patient to fall asleep. Therefore the patient will recall less about the procedure (laying in theatre, moments before procedure etc.) 

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

Some Barbituates such as Phenobarbital and Metharbital are effective for the treatment of generalised tonic-clonic seizures. 

Many Benzodiazepines such as Clonazepam, Nitrazepam, Lorazepam and Diazepam have anti-convulsant effects. Diazepam and Lorazepam can be used when treating status epilepticus. 

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

The benzodiazepines potentiate the effects of GABA. This leads to inhibition of the post-synaptic potential and consequently causes muscle relaxation.

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

 Sedative-hypnotics are CNS suppressive. The medulla oblongata, which is located in the brain, contains the respiratory and cardiovascular centres. Therefore when these drugs are administered, it suppresses the respiratory and cardiovascular system's function. If these drugs are abused, it can lead to death. 

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

- Voltage gated & Ligand-gated channels

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

Voltage gated channels: 

1. Changes in the membrane potential opens/closes the ion channel.

2. Specific for a certain ion. 

3. Sodium, Potassium and Calcium channels. 

Ligand-gated channels: 

1. Binding of a ligand (neurotransmitter) opens/closes the ion channel. 

2. Not specific.

3. Aceytl-choline, y-amino butyric acid, glutamate and serotonin receptors. 

Compare ionotropic and metabotropic receptors

Ionotropic receptors change shape when they are bound by a ligand, and this change of shape makes a channel that allows ions to flow through. This has a short duration of action. 

Metabotropic receptors do not have channels. They have a G-active protein that will activate a secondary messenger that will activate something else. This has a long duration of action (up to minutes).

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

There are only four ionotrpic receptors known. They are: 

- GABAa 

-Nicotinic 

-EEA

-5-HT3 

The metabotropic receptors include: 

- The adenylyl cylase system; B1+2, D1 = stimulates the formation of 2nd messengers (c-AMP)

; D2, a2, 5-HT1 A+B, M2, GABAb = formation of 2nd messengers is suppressed. 

- Phospholipase C system; a1, 5-HT2, M1 and H1 = stimulates the formation of 2nd messengers (IP3 and DAG)

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

EPSP  (Excitatory Post Synaptic Potential) - An electrical change (depolarisation) in the post synaptic membrane caused by the binding of an excitatory neurotransmitter from a presynaptic membrane will make it more likely for the post synaptic neuron to generate an action potential. An example of this would be when a neurotransmitter binds to Nicotinic receptor, Na+ channels open which causes depolarisation and has an activating effect. 

IPSP (Inhibitory Post Synaptic Potential) - An electrical charge (hyper polarisation) in the post synaptic membrane cause by the binding of an inhibitory neurotransmitter from the presynaptic membrane will make it less likely for the post synaptic neuron to generate an action potential. An example of this would be when neurotrasmitter binds to GABAa, Cl- channels open and causes hyper polarisation which has an inhibiting effect. 

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

Calcium ions trigger the release of neurotransmitters from the synaptic vessicle into the synaptic cleft. The synaptic vessicles fuse with the presynaptic membrane and exocytosis of the neurotransmitters occurs.