Briefly explain what cystic fibrosis is and how dornase alfa acts to solve the problem.

• Cystic fibrosis is a genetic defect leading to reduced secretions in various organs.

Dornase alfa (rhDNase I) hydrolyses extra-cellular DNA from the neutrophils in the bronchial mucus, increasing its liquidity drastically.

Briefly explain what neonatal respiratory distress syndrome is, what the general treatment strategies involve and how cortisone and exogenous surfactants solve the problem.

• Neonatal respiratory distress syndrome is when the surface-active material which covers the respiratory unit of the airways is not yet formed, resulting in disrupted gas exchange and the possibility that the lungs may collapse.

 The general treatment strategies include monitoring, oxygenation, continuous positive airway pressure and drugs.

These surfactants are administered exogenously or during acute respiratory distress syndrome to the neonate to augment lung surfactant.

A short course of corticosteroids is also effective to boost endogenous surfactant production.

Systemic administration of betamethasone to the mother just before labour can induce neonatal endogenous surfactant production within 24 hours.

What is the role of oxygen therapy in neonatal respiratory distress syndrome?  What do the dangers of oxygen toxicity involve?

• The role of oxygen therapy is to ensure oxygenation. Increased oxygen over long term leads to retinal damage and blindness.

Briefly explain what neonatal apnoea is and how the methylxanthines solve the problem.  Which methylxanthine is used?

• Neonatal apnoea occurs when the respiratory centre in the medulla of the premature baby has not yet developed sufficiently to stimulate continuous breathing.

Caffeine and theophylline

• What are the general causes of rhinitis and rhinorrhoea?

allergies, cold, chemical or drug damage, cold air or physical damage.

• Which drug groups can be used for the treatment of rhinorrhoea? Name examples from each group.
  1. α1-agonists – phenylephrine
  2. Antihistaminic and antimuscarinic drugs - Brompheniramine
  3. Corticosteroids - Prednisone
  4. Anti-allergy drugs – Sodium cromoglycate
  5. Mucolytics – Mesna
  6. Diverse Drugs – Normal salt solutions and volatile oils
• How do the decongestants differ with respect to the mechanism of action and duration of action?  How are they administered typically?

• Decongestants cause vasoconstricion of mucosal blood vessels that reduces oedema of nasal mucosa. Local Decongestants have fewer side effects, eg oxymetazoline (drops). Short acting drugs have a duration of 4 to 6 hours, intermediate acting drugs have a 8 to 10 hour duration and long acting drugs have a 12 hour duration.
• What is rhinitis medicamentosa?  How is it treated?

Rhinitis medicamentosa (privinism) is a condition that may present following chronic treatment with decongestants, where the permanent vasoconstriction with poor local blood supply leads to damage of the mucous membranes of the nose with permanent inflammation and swelling, as well as deregulation of the α-adrenergic receptors on the blood vessels, rendering them unresponsive towards the α-agonists.

It is treated by stopping the previous treatment and receiving local corticosteroids therapy

• How does the first and second generations of antihistamines differ with respect to the mechanisms according to which rhinitis and rhinorrhoea are relieved?  What are the advantages of the second generation of antihistamines?  Why should they not be used to relieve cold rhinitis?

• The first-generation antihistamines block muscarinic receptors.
• The second generation does not block the muscarinic receptors.
• The advantages of the second-generation antihistamine is that they are useful in the long-term or short-term treatment of allergic rhinitis.
• They should not be used to relieve cold rhinitis is because histamine plays no part in cold rhinitis.
• When are corticosteroids, anti-allergic drugs, mesna and normal salt solution valid and how are they administered? 

• Corticosteroid nasal sprays are weakly absorbed systemically, but can sometimes, in large doses, cause systemic side effects.
• Anti-allergic drugs - The use of sodium cromoglycate as a nasal spray is very effective for the prophylactic treatment of allergic rhinitis
• Mesna - Topical mesna (nasal spray) is especially meaningful to use when nasal secretion is sticky
• Normal salt solution – effective as nose drops. They are valid when humidification of dry, inflamed mucous membranes of the nose during colds, dry weather, allergy (hay fever), nose bleeding, overuse of decongestants and other irritations is necessary.

 Give your own definition of COPD.

Chronic bronchitis pulmonary disease is a chronic, inflammatory disease where the airways are hyper-responsive to stimuli that trigger the inflammatory process in the airways and lead to narrowing of the airways

• Briefly describe the proposed aetiology and pathophysiology of chronic bronchitis and emphysema.

The airflow limitation of COPD is believed to reflect an abnormal inflammatory response of the lung to noxious particles or gases. Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that causes obstructed airflow from the lungs. It is a condition involving constriction of the airways and difficulty or discomfort in breathing. Although asthma and COPD are both characterized by airway inflammation, reduction in maximum expiratory flow, and episodic exacerbations of airflow obstruction, most often triggered by viral respiratory infection.

• Which types of therapy are included in the treatment of a COPD patient?

ICPS therapy

Maintenance therapy

Oxygen therapy

• Why is ipratropium more effective in the treatment of chronic bronchitis than in the treatment of bronchial asthma?

Because it has an influence on the vagus nerve, it is a muscarinic Ach receptor antagonist which prevents the function of parasympathetic nervous system. The function includes: the production of bronchial secretions as well as constriction. If this is prevented it will result in bronchodilation and less secretions. Ipratropium is therefore more effective in the treatment of chronic bronchitis since it is characterized by increased mucus secretion. With bronchial asthma, the increased mucus secretion does not have the same effect.

• In which way do the skeletal muscle effects of theophylline have advantages in the treatment of COPD?

Theophylline improves the contraction function of diaphragm; therefore, it leads to an increase in patient’s ventilatory capacity.

• What is the role of oxygen therapy in COPD?

To improve airflow into the lungs thus improving breathing.

• 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). 

In a murine sepsis model, fluvoxamine was found to bind to the sigma-1 receptor in immune cells, resulting in reduced production of inflammatory cytokines.¹ In an in vitro study of human endothelial cells and macrophages, fluvoxamine reduced the expression of inflammatory genes.² Further studies are needed to establish whether the anti-inflammatory effects of fluvoxamine observed in nonclinical studies also occur in humans beings and are clinically relevant in the setting of COVID-19.

Fluvoxamine is a well-tolerated, widely available, inexpensive selective serotonin reuptake inhibitor that has been shown in a small, double-blind, placebo-controlled, randomized study to prevent clinical deterioration of patients with mild coronavirus disease 2019 (COVID-19). Fluvoxamine is also an agonist for the sigma-1 receptor, through which it controls inflammation. We review here a body of literature that shows important mechanisms of action of fluvoxamine and other SSRIs that could play a role in COVID-19 treatment. These effects include: reduction in platelet aggregation, decreased mast cell degranulation, interference with endolysosomal viral trafficking, regulation of inositol-requiring enzyme 1α-driven inflammation and increased melatonin levels, which collectively have a direct antiviral effect, regulate coagulopathy or mitigate cytokine storm, which are known hallmarks of severe COVID-19.

References

NIH, 2021. National Institute of Health. [Online]
Available at: http://www.covid19treatmentguidelines.nih.gov
[Accessed 18 Oct 2021].

PMC, 2020. PMC. [Online]
Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094534/
[Accessed 18 Oct 2021].

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

Endothelium-dependent vasodilation is when acetylcholine and bradykinin, act by increasing intracellular calcium levels in endothelial cells, leading to the synthesis of NO. NO diffuses to vascular smooth muscle, leading to vasorelaxation.

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 enzymes that are synthesized on a constant basis regardless of the physiological demand, so they have a greater physiological and pathological implication because they occur permanently in an area. Induced enzymes are enzymes that occur after a substance is added, so the enzyme is not present before the substance, which means that something has to be excreted by the body before that enzyme takes effect, so the implications are smaller.

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

Endotoxin components from the bacterial wall along with endogenously generated tumor necrosis factor-alpha and other cytokines induce synthesis of iNOS in macrophages, neutrophils, and T cells, as well as hapatocytes, smooth muscle cells endothelial cells and fibroblasts. This widespread generation of NO results in exaggerated hypotension, shock, and in some cases 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?

Phosphodiesterase enzymes that degrade cGMP, thus leading to NO having no or less effect.

NOS inhibitors and sGC inhibitor methylene bluein humans reduce or reverse the effects of NO.

NO is inactivated by reaction with oxygen to form nitrogen dioxide. NO reacts with superoxide to form peroxynitrite.

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

When challenged with foreign antigen, TH1 cells synthesis Nitric Oxide, the importance of NO of TH1 cell is demonstrated by the impaired protective response to injected parasites after inhibition of iNOS. NO also stimulates the synthesis of inflammatory prostaglandins by activating COX-2. Through its effects on COX-2, its direct vasodilatory effects, and other mechanisms, NO generated during inflammation contributes to the erythema, vascular permeability, and subsequent edema associated with acute inflammation. Excess NO production in acute or chronic inflammatory conditions may exacerbate tissue injury.

In which possible neurological and psychiatric diseases is NO involved?

Excessive NO synthesis is linked to excitotoxic neuronal death in several neurologic diseases including stroke, amyotrophic lateral sclerosis and Parkinson’s disease

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

Production of angiotensinogen is increased in corticosteroids, estrogens, thyroid hormones, and ANG II. It is further elevated during pregnancy and in women taking estrogen containing oral contraceptives. As a result, the increased plasma angiotensinogen concentration can lead 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 have a more complete blockage of the angiotensin system than ACE inhibitors, thus there is no increase in bradykinin, which leads to fewer side effects. The angiotensin blockers are also more selective than the non-selective ACE inhibitors, thus it will have less effects since the non-selective ACE inhibitors.

• In which way do ACE inhibitors have a two-fold mechanism of action in the treatment of hypertension?
  • ACE inhibitors decreases systemic vascular resistance without an increase in heart rate
  • ACE inhibitors inhibits bradykinin metabolism which causes hypotensive action.
• 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?
  • AT1 receptors
  • Yes, they do

• What are the physiological effects of kinins on arteries and veins?  Do other autacoids play a role in this action?  Explain.
  • Kinins produce arteriolar dilation and causes the veins to contract
  • Yes, other autacoids play a role. The vasodilation may result from a direct inhibitory effect of kinins on arteriolar smooth muscle or may be mediated by the release of nitric oxide or vasodilator prostaglandins such as PGE2 and PGI2. The veins contracting may e due to direct stimulation of venous smooth muscle or from the release of venoconstrictor prostaglandins.
• Which receptor is probably the most involved in the important clinical effects of kinins?

B2-receptor

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

They produce vasodilation and natriuresis.

• 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.

Neprilysin is the neutral endopeptidase NEP 24.11 that metabolizes natriuretic peptides in the kidneys, lungs, and liver. The inhibition of neprilysin results in an increase in ANP and BNP which causes natriuresis and vasodilation and an increase in renin secretion and plasma ANG II levels. The drug being used is sacubitril.

• Give examples of endothelium-derived vasodilators and vasoconstrictors. 

        Vasodilators: Nitric oxide and PGI2

         Vasoconstrictors: ET 1 and receptor subtypes ETA and ETB

PATHOLOGY OF MIGRAINE

Migraine is characterized by an aura of variable duration that may involve nausea, vomiting, visual scotomas or even hemianopsia, and speech abnormalities, the aura is followed by a severe throbbing unilateral headache that lasts for a few hours 1-2 days. Migraine involves the trigeminal nerve distribution to intracranial arteries. These nerves release peptide neurotransmitters, especially calcitonin gene-related peptide.

The mechanical stretching caused by this perivascular edema may be the immediate cause of activation of pain nerve endings in the dura. The onset of headache can also be associated with a marked increase in amplitude of temporal artery pulsations.

CURRENT TREATMENT AND THEIR MECHANISM OF ACTION

1. Triptans - are first line therapy for acute server migraine, they are selective agonist for 5HT1D and 5HT1B. They have a vasoconstriction action which prevents vasodilation and stretching of the pain endings.
2. Ergot alkaloids – activates 5-HT1D and 5-HT1B receptors on presynaptic trigeminal nerve endings to inhibit the release of vasodilating peptides. Its effect include agonist, partial agonist and antagonist action at alpha adrenoceptors and serotonin receptors and agonist or partial agonist actions at CNS dopamine receptors.
3. Nonsteroidal anti-inflammatory analgesic agents – helpful in treating migraine pain
4. Beta-adrenoceptor blockers and Calcium channel blockers – are migraine prophylaxis
5. Tricyclic antidepressants - activates 5-HT1D and 5-HT1B
6. SSRIs
7. Anti-seizures – suppresses excessive firing of these nerve endings
8. Anticonvulsants valproic acid and topiramate – it has some prophylactic efficacy in migraine.