STUDY UNIT 2.3 

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

Various factors including lipophilicity. This plays a major role in determining the rate at which a particular sedative-hypnotic enters the CNS

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

Highly lipid soluble drugs distribute to the brain, heart and kidneys immediately followed by muscle and fats it is quickly excreted and a depot is formed in fat or tissue where the drug will be slowly released.

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

Step by step biotransformation by hepatic microsomal enzymes.

1. Dealkylation: active metabolites
2. Oxidation: CYP450 active metabolites
3. Conjugation: Phase II of oxidised metabolite with glucuronic acid to form inactive metabolite.

• Which BDs are converted to active metabolites? What is the significance thereof?
  • • Diazepam
    • Chlorazepate
    • Prazepma
    • Chlordiazepoxide
    • Ketazolam

Active metabolites contribute to extended duration of action and cumulative effects with multiple doses. Important in elderly and neonates etc.

               

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

Oxazepam 

Lorazepam 

Tamezepam 

Lormetazepam 

Advantage is that they can act as drugs of choice in elderly, neonates, liver cirrhosis and therapy with P450 enzyme.

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

Study unit 3.3 

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

Microsomal ethanol-oxidising system

• What are the toxic effects of chronic alcohol consumption on the liver and hepatic metabolism?
• What is Wernicke-Korsakoff-syndrome and how is it treated?

The paralysis of the external eye muscles, ataxia, and a confused state that can progress to coma and death, it is also associated with a thiamine deficiency. The treatment is to receive thiamine therapy. 

• Fully explain the foetal alcohol syndrome.

It is the chronic maternal alcohol abuse during pregnancy and is associated with teratogenic effects. Alcohol is a leading cause of mental retardation and congenital deformation. The abnormalities that have been characterized as foetal alcohol syndrome include:

• Intrauterine growth retardation
• Microcephaly
• Poor coordination
• Underdevelopment of midfacial region 
• Minor joint abnormalities
• Congenital heart defects 
• Mental retardation

This happens because ethanol rapidly crosses placenta and reaches concentrations in foetus similar to that of maternal concentration, the foetal liver has little to no alcohol dehydrogenase activity.

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

Acute alcohol consumption will be metabolised through the alcohol dehydrogenase pathway whereas chronic consumption will be metabolised through the MEOS pathway.

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

Vasodilators 

Hypoglaecemic drugs 

Aspirin 

Disulfiram 

Metronidazole 

trimethoprim

STUDY UNIT 3.1

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

First-order and Zero-order kinetics. Alcohol is a small water soluble molecule and is absorbed rapidly in the GIT. Distribution is rapid with tissue levels approximating the concentration in blood. In the CNS, ethanol concentrations rise quickly because the bran receives a large portion from the total blood flow and ethanol readily crosses biological membranes.

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

1. Alcohol dehydrogenase pathway, this is the primary pathway of alcohol metabolism. It converts alcohol to acetaldehyde. These enzymes are found mainly in the liver but small amounts are found in the brain and stomach as well. This metabolic pathway can only meatbolise small to moderate amounts of alcohol

 (7-10g) due to the limited amount of NAD which also makes it a zero-order kinetic process.

2. Microsomal ethanol-oxidising systems, this type of metabolism is used fro high levels of alcohol consumption and in chronic alcohol consumption. Uses NADPH as a cofactor in the metabolism of ethanol. MEOS activity increases with chronic use and can be induced resulting in tolerance.

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

Disfulfiram 

Metronidazole

Hypoglycemic drugs 

Cephalosprorins 

These drugs, inhibit the oxidation of acetaldehyde, thus causing a build-up of acetaldehyde resulting in an unpleasant reaction such as. Nausea, vomiting, dizziness, headache etc.

STUDY UNIT 2.2-SEDATIVE-HYPNOTICS 

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

Anterograde amnesia, is the inability to remember events that occur during the drugs duration of action. Anterograde amnesia is caused by all benzodiazepines that are indicated for hypnosis to some degree. Some examples include; Lorazepam, temazepam, quazepam etc. 

• Name the effects of the sedative-hypnotic drugs on the normal sleep pattern and explain their significance to the patient.
  • • Decrease the time that it takes to fall asleep.
    • If the patient sleeps for less than 6 hours a night, it would increase total sleep duration.
    • Has a small suppressant effect on REM sleep, high dosages would increase suppression of phase 2 non-REM sleep
    • High dosages would also decrease the duration phase 4 non-REM sleep
    • If stopped, negative effects will be seen.

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

Benzodiazepines such as diazepam which has useful relaxant effects in skeletal muscle spasticity, Lorazepam to supress the symptoms of delirium tremens.

Phenobarbital can also be used in progressively decreasing doses to patients during withdrawal from physiologic dependence on ethanol or other sedative-hypnotics.

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

Benzodiazepines and Barbiturates

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

Exertion of inhibitory effects on polysynaptic reflexes and internuncial transmission and at high doses may also depress transmission at the skeletal neuromuscular junction. Selective actions of this type lead to muscle relaxation.

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

Respiratory:

At hypnotic doses in healthy patients, the effects on respiration are comparable to changes during the natural sleep pattern. Although, in patients with pulmonary disease, even at therapeutic doses, sedative-hypnotics can cause significant respiratory depression. Effects on respiration are dose related and depression of the medullary respiratory centre is the usual cause of death due overdose of sedative-hypnotics.

Cardiovascular:

In healthy patients, there are no significant effects observed on the cardiovascular system at doses up to those causing hypnosis. 

However, in hypovolemic states, heat failure and other diseases that impair cardiovascular function, normal doses of sedatives may cause cardiovascular depression, probably as a result of actions on the medullary vasomotor centres. 

At toxic doses, myocardial contractility and vascular tone may both be depressed by central and peripheral effects, possibly via facilitation of the cations of adenosine, leading to circulatory collapse. 

Respiratory and cardiovascular effects are more marked when sedative-hypnotics are given intravenously.

1. Types of ion channels found on nerve cells: 

• Voltage-gated channels 
• Ligand-gated channels

2. 3 differences between Voltage-gated channels and Ligand-gated channels:

Voltage-gated channels	Ligand-gated channels
Changes in membrane potential of the cell.	Binding of ligand to ion channel.
Transmits signal from the cell body to the nerve terminal.	Can be regulated by multiple mechanisms including phosphorylation and endocytosis.
Works with Sodium, Potassium and Calcium channels.	Very rapid action between binding of an agonist to the ligand-gated channel and a cellular response.

3. Comparison of ionotropic and metabotropic receptors: 

Ionotropic	Metabotropic
Ligand-gated ion channel receptors	7-Transmembrane G-protein coupled
Post synaptic potential	Production of second messengers that modulate ion channels
Works on multiple ion channels	Effects last longer as compared to ionotropic receptor activation.
Opening of ion channels	Metabolic changes
	G-protein dependant receptors

4. Classify CNS receptors into inotropic and metabotropic:

Ionotropic: 

• GABA_A ( g-amino butyric acid)
• Nicotinic (Acetylcholine)
• EAA (Glutamate)
• 5-HT₃ (Serotonin)

Metabotropic:

• Adenylyl cyclase system
• Phospholipase C system 

5. Difference between EPSP and IPSP: 

EPSP, excitatory post synaptic potentials-An electrical change such as depolarisation in the membrane of a postsynaptic neuron caused by the binding of an excitatory neurotransmitter from a presynaptic cell to a postsynaptic receptor thus making it more likely for a postsynaptic neuron to generate an action potential.

This is seen by, the Serotonin receptor causing depolarization in the sodium ion channel. 

IPSP, inhibitory postsynaptic potentials (IPSPs): a hyperpolarizing current that causes the membrane potential to become more negative.

This is seen with GABA receptors being hyperpolarized when opening of chloride channels.

6. Role of calcium in the development of synaptic potential: 

The release of a synaptic potential is dependant of calcium