What is paracetamol’s mechanism of action?How does it differ from Aspirin?

Peripherally: Weak COX-1 and COX-2 inhibitor. It is analgesic and antipyretic and it has no anti-inflammatory action. It does not any effect on platelet aggregation, unlike Aspirin. Aspirin also inhibits COX-1 and COX-2 irreversibly.

CNS: Blocks COX-3 and the %-HT descending pain pathways and it inhibits NMDA receptors, reducing nociception. This means neurotransmitters can't bind to receptors and the pain perception is blocked.

 

Name the indications for paracetamol.  Under which circumstances is it a drug of choice for the treatment of mild pain and fever? 

• It is used for the relief of mild to moderate pain of somatic origin
• Suitable for patients in which NSAID's are contraindicated
• It is the drug of choice for children
• Used when anti-inflammatory effect is not needed

 

Name side-effects that can occur with paracetamol use.  Concentrate only on general side effects and not on acute paracetamol overdose.

• skin rash
• urticuria

 

Compile a report in which you discuss acute paracetamol toxicity, stressing the dose, signs and symptoms and treatment.

Signs and symptoms: within 1-2 days:

• nausea and vomiting
• abdominal pain
• fatigue and weakness

Signs and symptoms: after 1-2 days:

• light subcostal pain
• tar liver
• jaundice
• liver necrosis
• death

 

Dose:

• 10-15g is a fatal dose
• Paracetamol poisoning can develop due to the chronic use of 2g a day

 

Treatment:

• Within one hour of overdose, induce vomiting or administer activated charcoal
• Liver damage can be prevented by administering NAC within 12 hours after overdose. 
• N-acetycystein administered IV within 8-12 hours
• Oral treatment: acetylcysteine or carbocistein
• Treatment is only effective within 10 hours of poisoning

Give a short and critical explanation of the rationale of using fluvoxamine (a selective serotonin reuptake inhibitor (SSRI) in the treatment of Covid patients. Your answer must be properly and appropriately referenced (in-text references as well).

Fluvoxamine is a SSRI( selective serotonin reuptake inhibitor) that is approved by the FDA for the treatment of depression, OCD and other conditions. However, the FDA did not approve it's use for infections such as COVID-19. (NIH,2021)

Studies that have been carried out shows that Fluvoxamine has a high affinity for the Sigma1 receptors of immune cells. This results in a decrease the production of inflammatory cytokines and inflammatory genes(NIH,2021) According to The Medical letter (Medical Letter, 2021 : 63) Sigma1 agonism inhibits SARS-CoV-2 replication. Theoretically Fluvoxamine prevents the development of a life threatening cytokine storm and acute respiratory distress syndrome in a COVID-19 infection.

 

Reference list:

• NIH (National institute of health). 2021. https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/

• Medical letter. 2021.https://secure.medicalletter.org/sites/default/files/freedocs/w1623d.pdf

What do you understand by the term “endothelium-dependent” vasodilation?  Explain.

It means vasodilation that takes place inside the endothelium. 

When we talk about the NOS enzyme, what is meant by “constitutive” and “inducible” enzymes and what are the pathological and physiological implications thereof?

Constitutive enzymes are continously synthesised, irrespective on if substrate is available or not. 

Inducible enzymes are released as a reaction to a stimulus. 

Because constitutive enzymes are continously produced they have a greater chance to be influenced by pathology than inducible enzymes. 

Explain how NO contributes to the fatal pathology of septic shock.

NO is produced during septic shock that causes vasodilation, which can cause the accumulation of blood in certain areas, hypotension and shock. This causes that less blood is available to important organs that can cause death. 

Which autacoids’ mechanism of action depends on effects on the guanylyl cyclase-cGMP system?

• Nitric oxide

NO may be toxic to the cell.  Which mechanisms are available to the body to counter this detrimental effect of NO?

NOS enzyme inhibitors are released by the body that binds competitively to argenine binding sites in NOS and prevents the conversion of argenine to NO.

Name a way in which NO can act pro-inflammatory.  Give examples of where it will have advantages or disadvantages.

When an alien antigen enters the body, NO is synthesised. This is advantageous because immune cells can reach the antigen and deactivate it, but it also has a negative impact because vasodilation can lead to anaphylactic shock. 

In which possible neurological and psychiatric diseases is NO involved?  

Parkinson's and stroke

Why do you think aspirin is contraindicated in people with allergic asthma?

Aspirin irreversibly blocks both COX1 and COX2, thus more arachidonic acid is available to produce leukotrienes. Thus more leukotrienes can be produced which leads to bronchoconstriction that has a negative effect on asthmatic patients. 

Arachidonic acid is the most important precursor of the eicosanoids, but how is this fatty acid released from the cell membrane, and by which stimuli?

Arachidonic acid must first be released from membrane phospholipids for eicosanoid synthesis to occur. 

There are three classes of phospholipases that contribute to the release of arachidonic acid from membrane phospholipids:

• cytosolic PLA ₂
• secretory PLA₂
• calcium independent PLA₂

Apart from prostanoids and leukotrienes, which other non-eicosanoid product of cell membrane hydrolysis is strongly involved in asthma?

Why would you say a COX II-inhibitor, and not a COX I-inhibitor, has a selective action in inflammatory reactions?

• COX1: "house-keeping" functions
• COX2: it is common in the kidney and it's release is due to inflammation, shear-stress and growth factors. 

A drug that inhibits each of the following enzymes: phospholipase A; cyclooxygenase; lipoxygenase,

• phospholipase A: hydrocortisone
• cyclooxygenase: Aspirin
• lipooxygenase: zileuton

A drug that can act antagonistically or agonistically at prostaglandin and leukotriene receptors.

• misoprostil

Aspirin inhibits platelet aggregation because it inhibits thromboxane synthesis and not prostacyclin synthesis.  How does it happen?

It happens because it irreversibly blocks COX1 and COX2

How is alprostadil advantageous in the treatment of congenital heart defects?

It is given to patients to keep their hert valves open during surgery.

How is misoprostil of value in the treatment and prevention of gastric ulcers?

It protects the gastric lining

Prostaglandin is possible of value in asthma.  Which PG_E2- or PGF_2A-analogues will be effective in such a case?

Epoprostal

How is latanoprost of value in the treatment of glaucoma?

It increases the outflow of aqueous humor

 

 

 

 

 

In which diseases are angiotensinogen levels increased?  What are the implications of this?

Hypertension. High levels of angiotensin lead to high levels of bradykinin that leads to vasoconstriction and ultimately leads to hypertension.

Why do drugs which inhibit the angiotensinogen system by acting on angiotensin receptors have fewer side effects than those that inhibit ACE?

Drugs that inhibit the angiotensinogen system causes a more complete blockage that the ACE inhibitors. Thus there are fewer side effects because there is less bradykinin. 

In which way do ACE inhibitors have a two-fold mechanism of action in the treatment of hypertension?

ACE inhibitors prevent the conversion of angiotensin 1 to angiotensin 2 that causes vasodilation. It also causes a decreased amount of aldosterone that will lead to decreased blood pressure. 

At which type of angiotensin receptor do losartan and similar drugs act?  Do they have any effect, direct or indirect, at other angiotensin II receptors?

Blocks angiotensin 2 receptors, they also have action on angiotensin 1 receptors.

What are the physiological effects of kinins on arteries and veins?  Do other autacoids play a role in this action?  Explain.

Kinins are potent vasodilators. Yes, Substance P and CGRP.

Which receptor is probably the most involved in the important clinical effects of kinins?

Bradykinin 2 receptors

In which way are natriuretic peptides possibly effective in the treatment of hypertension, as well as congestive heart failure?

They cause vasodilation and thus reduces the blood pressure. 

What is neprylisine and what is the rationale for inhibiting its action in the treatment of heart failure? Can you name the drug being used as such? Refer to Study unit 1 where you have also come across this drug.

It  that metabolizes ANP and BNP and causes an increase in glomerular filtration. This causes a decrease in blood pressure. The name of the drug is Sacubitril. 

Give examples of endothelium-derived vasodilators and vasoconstrictors.

• vasodilators: NO
• vasoconstrictors: ET1,2,3

 

Migraine Pathology:

Migraines are caused by the release of the peptide neurotransmitter that is related to the calcitonin gene (CGRP). This neurotransmitter causes vasodilation that activates the nerve endings in the brain and causes pain. 

Migraine treatment:

• Triptans are the first line of therapy for acute migraines. It prevents vasodilation and thus prevents the pain of the migraine. 
• Anti-inflammatory pain relievers can be a very useful treatment.
• Ergotamines causes vasoconstriction that can contradict the vasodilation of migraines.
• Beta blockers can also be effective in some patients to treat migraine prophylaxis.