BLOG #13

1. Discuss the possible mechanisms of action of lithium.

Lithium affects the IP3 and DAG 2nd messenger systems by reducing the activity of certain enzymes that are critical for the conversion and recirculation of membrane phosphoinositides.

2. What is the therapeutic index of lithium and what is its clinical significance?

Lithium has a therapeutic index of 0,5-1.5mM, which is very low. As a result, lithium dosing should be performed very carefully, and blood levels must be controlled to avoid lithium toxicity.

3. When is lithium used as a single drug and in which cases and with which type of drugs is lithium combined?

Lithium is used as a monotherapy for the prevention of depressive and hypomanic episodes, as well as the treatment of acute manic episodes. For the treatment of resistant or chronic unipolar disorder, as well as self-mutilating or destructive behaviour, lithium is combined with antidepressants.

4. Name 3 clinically significant interactions lithium may have with other drugs. Illustrate your answer with suitable examples of drugs.

Thiazide diuretics, new NSAIDs, ACE inhibitors, and fluoxetine can all lower renal clearance. Theophylline and caffeine improve lithium clearance in the kidneys. In combination with carbamazepine, calcium-blockers, losartan, methyldopa, metronidazole, and phenytoin, lithium is neurotoxic.

5. Name the major side effects of lithium.

Tremors, sedation, ataxia, aphasia, muscle weakness, fatigue, polydipsia, polyuria, nocturia, nephrogenic diabetes insipidus, thyroid enlargement, leucocytosis, oedema, weight gain, acne, alopecia, and sexual dysfunction.

6. What is the status of the use of lithium during pregnancy and lactation?

While lithium has been linked to an increased risk of congenital cardiovascular defects, the risk-benefit ratio is still favourable. Since lithium is excreted in high amounts in breastmilk, breastfeeding is not recommended.

7. Name three other important indications for lithium.

Lithium is used as a monotherapy for the prevention of depressive and hypomanic episodes, as well as the treatment of acute manic episodes.

8. Evaluate the following case and fully motivate your recommendations:

Ms B. Polar (21 years old, 60 kg) is a student who has been taking Camcolith 600mg bd for the past two months. After two weeks, the plasma levels were 0.8mmol/l. She has been taking Indocid® 75mg nocte for the past ten days due to a muscle injury. When questioned, she admits that she "had gained a lot of weight" and that she is now taking some of her mother's "water pills" in the hopes of losing a few pounds. She does, however, complain of exhaustion, having trouble holding her eyes open in class, being thirsty, and feeling weak and nauseous all of the time.

BLOG #12

1. Draw up a classification of the drugs that are used as antidepressants.

2. What do the existing drugs all have in common regarding their mechanisms of action?

Most of the drugs increase [NA] and [5-HT] at the central synapses. 

3. How long does it take for the antidepressive effects of these drugs to appear? What is the reason for this?

14-21 days- the onset of action 

3-5 weeks- clinical response

Multipotent actions on numerous monoaminergic receptors due to a non-specific increase in 5-Ht or NA. 

4. How do the TADs and the selective serotonin reuptake inhibitors (SSRI’s) differ in respect of: 

5. What is the action of mirtazapine?

Is a NaSSA: NA and specific serotonin AD. Blockade of a2, 5-HT 2A & 5- HT3. Also blocks H1, a1 and indirect stimulation of 5-HT 1A.

6. What is the action of venlafaxine?

Blocks both 5-HT and NA reuptake more potent for 5-HT than for NA.

7. What is the action of agomelatine?

Antagonist: 5-HT 2c

Agonist: Melatonergic receptors- MT1 and MT 2

BLOG #11

1. 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: least potent, produce more weight gain and sedation

Piperidine: least potent, produce more weight gain and sedation.

Piperazine: more potent, less sedation, exceptionally low hypotensive actions and high extrapyramidal effects

2. Which receptors are blocked by the typical antipsychotic drugs?

Dopamine 2 receptors

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

Atypical drugs block 5HT2A receptors more than they block D2 receptors. Whereas typical drugs block D2 receptors.

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

By blocking Dopamine 2 receptors there is a reduction in the risk of extrapyramidal effects. 

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

Piperazine has a high potency as well as Dopamine 2 receptor affinity.

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

Muscarinic receptors blockade.

BLOG #10

1. Which two main groups of drugs are important in the treatment of parkinsonism? 

Dopamine agonists and anticholinergic drugs. 

 2. In what way does amantadine act as an anti-parkinsonism drug?

Amantadine enhances dopaminergic neurotransmission by unknown mechanisms that involve increasing synthesis or release of dopamine or inhibition of dopamine reuptake. The drug also has muscarinic blocking actions. Amantadine improves bradykinesia, rigidity, and tremor. It also has antiviral effects. 

3. Discuss the mechanisms of action of the anti-parkinsonism drugs that indirectly increase dopamine concentration.

Monoamine Oxidase Inhibitors ( Selegiline and Rasagiline): These are selective inhibitors of monoamine oxidase type B, the form of the enzyme that metabolizes dopamine. This indirectly increases dopamine concentrations by preventing its metabolism. Hepatic metabolism of Selegiline results in the formation of desmethylselegiline (neuroprotective) and amphetamine. 

Catechol-O-methyltransferase Inhibitors (Entacapone and Tolcapone): COMT is the enzyme that converts Levodopa to 3-O-methyldopa. These drugs inhibit COMT, thereby increasing the concentration of Levodopa. 

Amantadine: this drug inhibits the reuptake of dopamine, thereby indirectly increasing the concentration of dopamine. 

4. Which dopamine agonists are ergot derivatives and which are not?

Ergot derivatives: Bromocriptine

Non-ergot derivatives: Pramipexole and Ropinirole

5. List the specific dopamine receptors that are stimulated by each agonist.

D2 receptor agonists:

-Ropinirole

-Bromocriptine

D3 receptor agonists:

-Pramipexole

6. Which of these drugs are classified as neuron protecting drugs?  What does this mean?

Selective Monoamine Oxidase B (MAO-B) inhibitors (eg Rasagiline). This means that the MAO-B inhibitor prevents MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) from being converted to MPP + (N-methyl-4-phenylpyridium), which can therefore protect against the prevalence of Parkinsonism.

7. What is the importance of monoamine oxidase B (MAO-B) selective drugs in the treatment of Parkinsonism?

These drugs work with drugs such as Levodopa. MAO-B inhibitors prolong the duration of the effects of Levodopa.

8. How do the COMT-inhibitors act in Parkinsonism?

COMT inhibitors metabolize L-dopa to 3-O-methyl dopa (30MD), the increased levels of 3OMD leads to a weak therapeutic response with L-dopa. 30MD competes with L-dopa for active transport processes. These drugs increase the duration of L-dopa thus, decreasing peripheral metabolism and improving the bioavailability of the drug.

9. How does Istradephyline act?

This drug inhibits Dopamine 2 functioning by antagonising adenosine activity preventing the inhibition of dopamine functions. It is an additional therapy to L-dopa or carbidopa therapy that experiences on-off episodes.

BLOG #9

1. How does the sensitivity for blockade by a LA compare regarding the following types of fibres:

(a) myelinated fibres with unmyelinated fibres:

Smaller myelinated fibres are blocked easier than larger unmyelinated fibres. 

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

Fibres in the middle of a thick nerve bundle is blocked slower than those at the outside of the bundle. 

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

Heart: Class 1 anti arrhythmic drugs block the sodium channels in the heart with the goal of blocking the propagation of an action potential and prolonging the refractory period. 

Skeletal muscles: LA have very weak blocking action therefore are not used in clinical application. 

3. What is the basis for the selection of a LA?

Systemic or localized distribution and absorption. 

4. Why are LA solutions sometimes saturated with CO₂?

To lower the pH of the blood during the use of LA. 

5. Which of the LA are typically used for surface anaesthesia?

Benzocaine 

Cocaine 

Oxybuprocaine 

The major acute toxic effects of inhalation drugs: 

• Nephrotoxicity
• Hematotoxicity
• Hepatotoxicity

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?

1. Phenobarbital
2. Oxacarbezpine
3. Topiramate
4. Carbamazepine
5. Phenytoin

Oral contraception effectiveness is reduced by these medications. The following drugs are safe to take with the Pill: Valproate, Lamotrigine, Gabapentin, Levetiracetam and Vigabatrin.

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

Yes. Valproate and lamotrigine plasma concentrations are reduced by oral contraceptives.

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

The metabolism of these drugs is slow in neonates. In children, these drugs are metabolized faster than in adults. Since elderly people's kidney function is impaired, they should be given a lower dose.

In which cases is plasma blood level monitoring indicated?

1. During pregnancy
2. When breakthrough seizures occur
3. To guide dose adjustment
4. When an interacting medication is added or removed from the patient's regime 
5. To assess adherence
6. To determine whether adverse effects are related to drug levels.

What are the possible mechanisms involved in the development of tolerance to chronic alcohol consumption?

Microsomal ethanol oxidation (MEOS) activity increases with the chronic use of alcohol and can be induced and is partly responsible for alcohol tolerance.

What toxic effects does chronic alcohol use have on the liver and liver metabolism?

There is a decrease in gluconeogenesis that indicates hypoglycemia and fat accumulation, nutrient deficiencies also contribute to the above. There is increased activity of liver microsomal enzymes. There ʼn progressive reduction in liver function, hepatitis & cirrhosis can occur. Damage to liver function is worse in women than men.

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

It is accompanied by neurological damage to the lower part of the brain, thalamus and hypothalamus. This syndrome can be caused by the deficiency of thiamine- Vitamin B1. The syndrome causes chronic memory disorders. Symptoms of Wernicke-Korsakoff syndrome are: Confusion, paralysis of facial muscles and ataxia.

Parenteral thiamine can be administered to prevent permanent brain damage.

What is fetal alcohol syndrome? Explain in full.

This is the syndrome that occurs in a mother's baby during the mother's chronic alcohol use during her pregnancy. The fetus in the uterus was constantly exposed to the alcohol. Teratogenic effects occur in this syndrome. The syndrome certainly includes features such as: mental retardation, microcephaly, growth defects, characteristic underdevelopment of the middle facial area.

How do the pharmacokinetic interactions of acute and chronic alcohol use differ?

In chronic alcohol use, metabolic transformation of other drugs increases with acute alcohol use, there is a reduced metabolism of drugs, e.g. Phenotia, TADs and others sedative-hypnotic drugs.

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

1. Hypoglycemic agents

2. Blood pressure lowering drugs

3. Paracetamol

4. Vasodilators.

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

Ethanol has a zero-order kinetic uptake, which ensures that it is absorbed from the bloodstream at a steady rate. This means that the amount you ingest will last in the body for longer if you drink it rapidly. Since the alcohol does not have enough time to leave the body, the blood alcohol levels can increase quickly, causing an impact.

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

Alcohol dehydrogenase and coenzyme NAD, as well as MEOS and coenzyme NADPH, convert ethanol to acetaldehyde. Aldehyde dehydrogenesis will then convert acetaldehyde to acetate.

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

The drug fomepizole inhibits alcohol dehydrogenase, preventing the development of acetaldehyde. Aldehyde dehydrogenase can be blocked by medicines like disulfiram, metronidazole, cephalosporins, and hypoglycemic drugs, preventing the formation of acetate. Acetaldehyde build up may cause symptoms including nausea, vomiting, headaches, and fire.

Herbal and botanical drugs that are used to treat anxiety and insomnia.

1. Ashwagandha
2. Kava-kava
3. Valerian
4. Cinnamon
5. Chamomile
6. Lemon Balm
7. Ginseng
8. Hops