1. 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?

Perampenel (decreases the efficacy of levonorgestrel-containing contraceptives) and Phenobarbitone, phenytoin, carbamazepine, and oxcarbazepine all reduce the effectiveness of the oral contraceptive pill, resulting in more births and the risk of teratogenic effects in these pregnancies. Valproate, Lamotrigine, Gabapentin, Levetiracetam, and Vigabatrin are all safe to take together.

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

Yes, oral contraceptives can lower the levels of drugs like Lamotrigine and Valproate in the blood.

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

Since neonates have a slower metabolism, they should be given lower doses. Since babies and children's metabolisms are quicker than adults', they should be given higher doses. Because of their slower metabolism and reduced renal activity, geriatric patients need lower dosages.

4. In which cases is plasma blood level monitoring indicated?

Chronic kidney failure, liver disorders, hypoalbuminemia, burns, pregnancy, malnutrition, age, and the use of displacement drugs are all examples of where protein binding occurs and some diseases that may cause protein binding. Plasma blood level monitoring is needed in these situations.

Many patients would rather use dietary supplements (e.g. herbal supplements) as they have the notion that it is safer because it is natural products, however some side effects may come with these medicines.

Herbal remedies for treating anxiety:

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

Herbal remedies for treating insomnia:

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

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

Tolerance can develop as a result of ethanol-induced upregulation of a pathway in the presence of ethanol. Furthermore, because of the downregulation of GABAA mediated receptors with continued alcohol use, the GABA neurotransmitter plays a role in tolerance. Continuous use of alcohol can cause the same pathway to become overactive, resulting in dependence.

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

Chronic alcohol intake impairs liver function, resulting in diseases such as hepatitis and liver cirrhosis. Increased activity at this pathway may also have metabolic consequences from ethanol oxidation. Chronic alcohol intake can also slow down processes including gluconeogenesis, resulting in hypoglycemia.

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

Wernicke-Korsakoff syndrome is characterized by weakness of the external eye muscles, ataxia, and a confused condition that can lead to a coma when caused by Thiamine deficiency. Parental thiamine therapy is part of the treatment.

4. Fully explain the foetal alcohol syndrome.

The ethanol ingested by the mother crosses the placenta, causing the foetus to have the same alcohol blood content as the mother. Foetal alcohol syndrome is caused by a mother's alcohol consumption while pregnant. Mental retardation and underdevelopment of the facial area are common in infants with this syndrome, which is usually teratogenic.

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

Acute – the alcohol dehydrogenase enzyme, which catalyzes the conversion of alcohol to acetaldehyde, plays a role with low to moderate levels of alcohol intake.
Chronic - on the other hand, the MEOS plays a role of high-concentration alcohol intake since their behaviour is caused by chronic alcohol consumption.

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

Under the influence of acute alcohol intake, the metabolism of phenothiazines, TCAs, and sedative hypnotics such as benzodiazepines is reduced or inhibited due to a reduction in enzyme activity and liver blood flow. Acute alcohol intake potentiates the effects of vasodilating and hypoglycemic medications, resulting in extreme vasodilation in the body, resulting in a decrease in blood pressure and increased heart rates to maintain vital organ function. Aspirin's anti-platelet aggregation effects are enhanced by alcohol.

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

Alcohol is a water-soluble molecule that is quickly absorbed from the gastrointestinal tract. Alcohol's high lipophilicity allows for rapid passage through the blood-brain barrier and into the central nervous system. In a fasting state, peak alcohol levels in the blood can be seen within 30 minutes of intake. The total fluid in the body plays an important role in alcohol distribution; the more body fluids there are, the longer it takes for the alcohol concentration to reach toxic levels. The liver (90 percent of the time) metabolizes alcohol using two enzyme systems: Alcohol Dehydrogenase and MEOS (mixed function oxidases).

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

The Alcohol Dehydrogenase System and MEOS are the two enzyme systems in the liver that are responsible for the metabolism of alcohols (ethanol).
The Alcohol Dehydrogenase system uses zero-order kinetics to catalyze the conversion of alcohol to acetaldehyde, resulting in the pathway becoming saturated and independent of ethanol concentration. This pathway uses NAD as a co-enzyme to metabolize low to moderate levels of alcohol [7-10g/h]. The Microsomal Ethanol-oxidizing Mechanism (MEOS) is in charge of converting ethanol to Acetaldehyde at higher concentrations [>100mg/dL]. Its activity can be caused by consuming alcohol on a regular basis. Aldehyde-dehydrogenase transforms acetaldehyde to acetate, which is then broken down into carbon dioxide and water and excreted through the urine or used to make Acetyl Co-A.

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

Disulfiram, metronidazole, cephalosporin, and hypoglycaemic drugs are all drugs that affect alcohol metabolism. As a result of the drug's inhibition of Aldehyde Dehydrogenase, the body accumulates Acetaldehyde. Acetaldehyde concentrations in the body can induce the same harmful effects as heavy drinking, such as nausea, vomiting, ataxia, headaches, and so on.

References:

Katzung, B.G. 2018. Basic and Clinical Pharmacology. 14th ed. United States of America: McGraw-Hill Education.

1. What factors may effect the absorption and distribution of sedatives-hypnotic drug? What is the clinical significance thereof?

Due to highly lipophilic nature of the Blood Brain Barrier (BBB) the most important factor of absorption and distribution of sedative hypnotic drugs are the lipophilicity of the drugs. Also, the lipophilicity of the drugs effects the onset of action of the drugs. Drugs with a high lipophilicity easily cross the BBB and exert much more easily an effect on the CNS.

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

The redistribution of drugs is the absorption of drugs (high lipophilicity) in the systemic circulation and distribution of it to other organs such as the brain heart and kidneys. Then after it goes into muscle and fatty tissue forming a depot effect which result in a longer duration of the drug which is also the importance of redistribution.

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

BDs are metabolised by the hepatic microsomal enzymes. 

• Step1: Dealkylation to active metabolites. Also desmethyldiazapam is formed.
• Step 2: Microsomal Oxidation by CYT P450 enzymes to an active metabolite. Active metabolite desmethyldiazapam gets oxidised resulting in Oxazepam.
• Step 3: Conjugation (phase II) of the Oxazepam metabolite with glucuronic acid to form an inactive metabolite forming glucuronides, which are water-soluble and are excreted in urine

4. Which BDs are converted to active  metabolites? What are the importance of that?

Diazepam, Cholarazepam,  Prazepam, Chlorodiazepoxide, ketazolam. It lengthens the duration of action of the drugs.

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

Oxazepam, Lorazepam, Temazepam, Lormetazpem. It's beneificial to those patients having liver cirrhosis, elder people, neonates, and patients are on CYP-P450 inhibtors.

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

When a drug increases the production of an enzyme which increases their rate of of metabolism. Barbiturates and meprobamate are known for this. This means the drug has a great metabolism rate  which lead to a lesser concentration of the drug in the circulation system, finally decreasing the therapeutic effect.

Bertram G. Katzung 2018, B Basic & Clinical Pharmacology, Lange, McGraw hill, University of California, San Francisco.

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

Inability to remember events occurring during the drug's duration of action. Drugs that exert this effect are the BD's.

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

Decreases the time it takes to fall asleep. This is beneficial for patients who struggle to fall asleep.

Increases the amount of hours you sleep. This help patients who usually can't sleep more than 6 hours sleep longer.

Changes in sleep structure. Increases or decreases a certain sleep stage or more.

3. Which of the sedative-hypnotic drugs are used as a supplementary therapy in anaesthesia. Explain why.

Midazolam, Diazepam, Lorazepam. These are sedative drugs and aids in keeping the patient sedative while the operation occurs.

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

clonazepam, diazepam, lorazepam, clobazam, phenobarbitone, nitrozepam 

5. What is the mechanism of the muscle-relaxing effects of some of the carbamates and the BS's?

Inhibition of polysynaptic reflexes and internuncial transmission leading to the depression of the skeletal neuromuscular junction.

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

Respiratory system: leads to respiratory depression in pulmonary diseases. Also effects on respiration are dose related and overdose could lead complete depression on the medullary respiratory center which can be fatal.

Cardiovascular system: leads to cardiovascular depression in cardiovascular diseases with high doses

References: Bertram G. Katzung 2018, B Basic & Clinical Pharmacolog, Lange, McGraw hill, University of California, San Fransico.

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

Voltage-gated and Ligand-gated channels

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

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

IPSP: When an inhibitory pathway in the CNS is stimulated by γ-aminobutyric acid (GABA) binding to a GABA receptor and stimulating the receptor, the post synaptic potential is hyperpolarised due to the selective opening of chlorine channels so that an inhibitory post synaptic potential can be developed which will eventually "suppress" the CNS. e.g., EAA.

EPSP: When an excitatory path is stimulated, because eg. glutamate binds to the NMDA receptor and it stimulates depolarization which will result in an excitatory membrane potential.

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

Calcium is responsible for the release of neurotransmitters by means of depolarization of the cell membrane when action potential arrives at the axon terminal.