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

Cystic fibrosis is a genetic metabolic disease with reduced DNase I concentration that cause a reduction in secretions in various organs. The airways display the worst symptoms. The mucus becomes so thick and sticky, that it causes recurrent bacterial infections. The body does not have the ability to remove this mucus.

Dornase alpha (which is rhDNase I) inhalations hydrolyze the proteins in bronchial mucus and makes the mucus more fluid so that it can be more easily removed.

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

Also called hyaline membrane disease. It is found in premature babies when the surfactant that covers a normal person's airways which are responsible for gas exchange are not present (this surfactant is produced just before birth and are therefore not present in a premature baby). The lungs can fall flat (atelectasis) which is fatal.

Treatment strategies:

Monitoring respiratory and circulatory function, is essential.

Oxygen ensures oxygenation (but do not use too long because can cause retinal damage and blindness)

Ventilation ensures positive pressure

Exogenous surfactants such as beractant or poractant alpha which provides surfactant so that gas exchange can take place an the lungs don't collapse.

Corticosteroids such as betamethasone administered systemically (orally) prophylactically to the mother before labour to induce the surfactant reproduction of the baby/initiate the baby's surfactant reproduction.

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

It provides oxygenation which makes up for the impeding gas exchange.

Retinal damage that cause blindness.

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

The respiratory center in the medulla is not yet fully developed to stimulate continuous breathing in neonates and premature babies. Apnoea together with bradycardia happens longer than 15 seconds and repeatedly. This cause hypoxia and neural damage.

Methylxanthines (theophylline and caffeine IV for weeks) stimulate the CNS.

• What are the general causes of rhinitis and rhinorrhoea?

Allergies, colds and flue, cold air, physical damage, chemical or drug damage.

 

• Which drug groups can be used for the treatment of rhinorrhoea? Name examples from each group.

First generation antihistamines: diphenhydramine, promethazine, chlorpheniramine, brompheniramine

Alpha 1 agonist/decongestants: phenylephrine, ephedrine, phenylpropanolamine, naphazoline, xylometazoline, oxymetazoline

 

• How do the decongestants differ with respect to the mechanism of action and duration of action?  How are they administered typically?

Ephedrine, pseudoephedrine and propylhexidrine are non-selective for adrenoceptors and thus stimulate alpha and beta adrenoceptors with a potent indirect action and mixed action.

Phenylephrine is direct acting.

Naphazoline, xylometazoline and oxymetazoline are imidazole derivatives with mixed action.

They are administered as nasal sprays, gels/jellies, drops and inhalations.

Short acting (4-6 hours): ephedrine, phenylephrine, naphazoline

Intermediate acting (8-10 hours): xylometazoline

Long acting (more than 12 hours): oxymetazoline

 

• What is rhinitis medicamentosa?  How is it treated?

It happens when decongestants/alpha 1 agonist are used chronically.

The permanent vasoconstriction of nasal capillaries and reduced blood supply to the nasal mucosa/nasal walls, damages the nasal mucosa which cause permanent swelling and inflammation of the nasal walls. Alpha 1 receptor deregulation also happens which leads to the receptors not acting on alpha 1 stimuli. Tachyphylaxis (depletion of l-NA) also occur.

Treatment: Corticosteroid/cortisone nasal sprays such as beclomethasone.

 

• 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?

First generation antihistamines only relieve rhinorrhoea caused by colds. They are multipotent antagonists which also antagonizes muscarinic receptors and thus reduce mucus secretions/mucus production in the upper and lower airways.

Second generation antihistamines only relieve allergic rhinitis. They only antagonize histamine 1 receptors which has an anti-inflammatory effect. The second generation drugs to not cause sedation or reduced concentration and can be used in prophylactic/chronic treatment of allergic rhinitis.

They should not be used to relieve cold rhinitis because they do not have an effect on bradykinin receptors (bradykinin and not histamine are released during colds and thus bradykinin receptors and not histamine receptors should be blocked).

• When are corticosteroids, anti-allergic drugs, mesna and normal salt solution valid and how are they administered? 

Corticosteroids (nasal drops/topical): allergic rhinitis, inflammatory rhinitis, nasal polyps, reversal of rhinitis medicamentosa/privinism

Anti-allergic drugs/mast cell stabilizers (topical): prophylaxis of allergic rhinitis

Mesna (topical/nasal sprays): diluting sticky nasal mucus

Normal salt saline solution (topical/nasal sprays): nasal lavage to dilute mucus caused by sinusitis.

• Give your own definition of COPD.

COPD consist of different degrees and combinations of bronchial asthma, chronic bronchitis and emphysema.

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

Chronic bronchitis:

Aetiology is unknown (idiopathic).

It is a non-specific obstructive disease where there are an increase in mucus production/secretion and a decrease in mucus clearance. The bronchial walls undergo structural changes, frequent respiratory bacterial infections occur and a chronic cough due to sticky mucous occur.

Emphysema:

Aetiology is smoking, irritants and those who are susceptible because of an alpha 1 antitrypsin deficiency.

It is the irreversible dilation of respiratory bronchioles and alveoli due to structural changes. Air gets trapped in the lungs and are exhaled with difficulty. There are also a decrease in capillary blood vessels which further impedes gas exchange.

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

Anticholinergics: Ipratropium and tiotropium (or long acting: glycopyronium bromide)

Bete 2 stimulants and/or slow release theophylline

Corticosteroids sometime used but not usually well tolerated

Oxygen therapy

Acute illness: hospitalization, antibiotics, physiotherrapy

Cessation of smoking

Bacterial infections: yearly influenza immunization or broad spectrum antibiotics (tetracyclines, ampicillin, amoxicillin, erythromycin, cotrimoxazole)

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

Chronic bronchitis is due to irritants that stimulate the vagus reflex which cause an overactive parasympathetic nervous system while asthma is due to sympathetic and parasympathetic effects. Ipratropium which is an anticholinergic drug and parasympatholytic will thus be more effective in bronchitis and not in bronchial asthma as although some effect will be seen because of inhibition of the parasympathetic nerve system, the sympathetic nervous sytem will be unopposed thus asthma symptoms will not be entirely reduced by ipratropium.

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

It strengthens the contraction of diaphragm skeletal muscles which improves the ventilation response/ventilation capacity, reduce the hypoxia and reduce the dyspnea associated with COPD.

• What is the role of oxygen therapy in COPD?

It reduce the symptom of hypoxia associated with COPD.

Rationale for using Fluvoxamine (=SSRI) in the treatment of Covid-19 patients:

Fluvoxamine binds to the sigma-1 receptor and stimulates this receptor which is found in immune cells (NIH, 2021). This leads to decreased synthesis of pro-inflammatory cytokines (interferon gamma, tumor necrosis factor alpha, interleukin-1, -2, -6, -12 ). Covid-19 is referred to as the cytokine storm with widely distributed inflammation all over the body.  Fluvoxamine can thus be useful as it is anti-inflammatory through reducing cytokine synthesis. 

Reference list:

1.  NIH (National Institutes of Health). 2021. Fluvoxamine COVID-19 treatment guidelines. https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/ Date of access: 27 Oct. 2021

 

 

 

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

Endothelium cells respond to vasorelaxants by releasing soluble endothelium-derived relaxing factor (EDRF). EDRF acts on vascular muscle to cause relaxation. NO is the major bioactive component of EDRF.

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

iNOS are expressed through transcriptional induction (inducible) when exposed to inflammatory mediators and this expression, and thus NO synthesis, is not regulated by calcium. eNOS and nNOS are expressed constituvely (=continuously produced regardless of cells' needs) and NO synthesis is dependent on calcium regulation. Cytosolic calcium forms complexes with calmodulin which then binds and activates eNOS and nNOS.

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

Sepsis is a systemic inflammatory response caused by infection. Endotoxins from the bacterial cell wall along with endogenously generated TNF-alpha and other cytokines, induce synthesis of iNOS in macrophages, neutrophils, T-cells, hepatocytes, smooth muscle cells, endothelial cells and fibroblasts. This widespread synthesis of NO cause aggravated hypotension, septic shock and death. 

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

NO

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

Intracellular glutathione protect against tissue damage caused by scavenging peroxynitrite (peroxynitrite=NO+superoxide; it inhibits protein function and cause tissue damage during inflammation).

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

NO stimulates the synthesis of inflammatory prostaglandins by activating COX-2. The vasodilatory effects of prostaglandins along With NO leads to an increase in vascular permeability and thus lead to perivascular oedema. Excessive NO production may lead to tissue injury (iNOS induction.)

• In which possible neurological and psychiatric diseases is NO involved? 

- Stroke

- Parkinson's disease

-  Amyothropic lateral sclerosis

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

Hypertension.

An increase in angiotensinogen cause an increase in conversion to angiotensin I through renin. ACE (angiotensin converting enzyme) converts angiotensin I to angiotensin II which activates angiotensin II type 1 receptors. This cause vasoconstriction ( and an increase in peripheral resistance and BP), an increase in aldosterone secretion (increased Na and H2O reabsorption and increased bood volume) and cardiac hypertrophy and remodelling which will aggravate hypertension further. This can lead to heart failure.

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

Drugs which blocks ACE will also lead to the inhibition of bradykinin breakdown. Increased bradykinin concentrations cause bradykinin 2 receptor mediated bronchoconstriction (a vagal cough reflex) which cause the negative side-effect of a dry, irritating cough.

Drugs which act specifically on angiotensin receptors will not inhibit bradykinin breakdown and thus will not have this adverse effect because; [bradykinin] will not be increased.

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

ACE inhibitors firstly block the conversion of angiotensin I to angiotensin II. Angiotensin II type I receptors are also blocked. This leads to vasodilation instead of vasoconstriction which leads to a decrease in peripheral resistance and BP. Aldosterone secretion decreases which leads to less salt and water retention and more excretion which lowers cardiac preload, decrease cardiac output and decrease BP. Left ventricular hypertrophy is also reversed.

ACE inhibitors also inhibit bradykinin breakdown. Increased bradykinin concentrations, increase prostaglandin synthesis which increase arterial vasodilation, lowers peripheral resistance and lowers BP. This is all therapeutically useful in hypertension.

• 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?

They act on angiotensin II type 1 receptors. They have no affect on angiotensin II type 2 receptors.

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

Kinins cause vasodilation of arteries and vasoconstriction of veins. Yes, there are many other autacoids that also cause vasodilation; Natriuretic peptides, vasoactive intestinal peptides, substance P, neurokinin A, neurokinin B, Calcitonin gene-related peptide.

• 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?

Natriuretic peptides cause vasodilation which decrease peripheral resistance and decrease BP that can be effective in treating hypertension.

Natriuretic peptides increase glomerular filtration and sodium excretion, decrease renin secretion, decrease sodium reabsorption and decrease the effect of angiotensin and aldosterone. This will relieve the oedema associated with congestive heart failure.

• 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 metabolizes the natriuretic peptides ANP and BNP which lead to a decrease in their concentrations. In reducing ANP and BNP, their positive therapeutic effects in congestive heart failure is also reduced (less vasodilation and rather vasoconstriction,  decreased glomerular filtration and sodium excretion, increased renin secretion, increased sodium reabsorption and increased effect of angiotensin and aldosterone). Thus neprilysin should be blocked so that the therapeutic positive effects of ANP and BNP can dominate.

Neprilysin inhibitor drug: Sacubitril

• Give examples of endothelium-derived vasodilators and vasoconstrictors.

Endothelium derived vasodilators: PGI2, NO (nitric oxide)

Endothelium derived vasoconstrictors: ET1, ET2, ET3, ETA, ETB

Endothelium antagonists that cause vasodilation: Bosentan, macitentan, ambrisentan, sitaxsentan.

Migraine

Pathology

Migraine involves the release of the peptide neurotransmitter, calcitonin gene-related peptide (CGRP), from nerves distributed in cerebral arteries.  This neurotransmitter causes vasodilation and extravasation of blood plasma and plasma proteins into the perivascular space (perivascular oedema).  This causes a mechanical stretching which in turn lead to the activation of pain nerve endings in the dura.

Current treatments

Triptans (e.g. Sumatriptan) are first-line therapy for migraines. They are partial agonists at serotonin 1B/1D receptors and increase intracranial vasoconstriction that prevents the above-mentioned vasodilation that causes pain due to the stretching of sensory nerve endings. These agents may also reduce the release of CGRP and as a result also reduces perivascular oedema in the intracranial circulation.

Ergot alkaloids (e.g. Ergotamine and Ergonovine) have mixed partial agonist effects at serotonin 2 receptors and alpha adrenoceptors. They cause marked smooth muscle contraction but blocks alpha-agonist vasoconstriction. These agents therefore also prevent the above-mentioned vasodilation that leads to pain.