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

Cystic fibrosis is a genetic metabolic disease which leads to decreased secretions in various organs and where the body lacks the ability to clear mucus. In the airways the mucus secretions are thick and sticky which can lead to bacterial infection. 
Dornase alfa hydrolyses extra-cellular DNA from the neutrophils in the bronchial mucus, increasing its liquidity. Hydrolyses protein in bronchial mucus to improve fluidity. (Inhaled)

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

It is when the surface acting agent (surfactant which covers airways and is essential for gaseous exchange is only formed shortly after birth. 
The general treatment includes:
Monitoring: Respiratory and circulatory status
Oxygenation, continuous positive airway pressure:
Oxygen is administered to ensure oxygenation
Positive pressure improves respiration and keeps alveoli open to prevent it from collapsing. Arterial oxygen pressure must be monitored
Drugs: Exogenous surfactant, corticosteroids and Betamethasone.

Corticosteroids:
Boosts endogenous surfactant production, it is also a cheaper alternative to exogenous surfactant. 
When the baby is viable and there is an impending miscarriage it can be administered prophylactically. Administered to mother to initiate baby's surfactant production.

Exogenous surfactant administered prophylactically to increase lung surfactant. 

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

Oxygen is administer to ensure oxygenation. The dangers involve retinal damage and blindness with long term use. 

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

It is when the respiratory centre in the brain is not fully developed to stimulate continuous breathing. Methylxanthine stimulates the CNS and as a result, stimulates the breathing centre, regular breathing rhythms can be maintained. Theophylline and caffeine are used IV for a few weeks.

• What are the general causes of rhinitis and rhinorrhoea?

Usually caused by: Allergy, cold, chemicals, drugs or physical damage.

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

α1 agonists (decongestants) phenylephrine
Antihistamines: diphenhydramine
Corticosteroids: Betamethasone
Mast cell stabilisers: Ketotifen
Mucolytics: Mesna
Diverse drugs: Saline
Antibiotic: Neomycin

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

These are sympathomimetic agents which work by agonism on α1 receptors, causes vasoconstriction of the mucosal blood vessels, a decrease in oedema of the nasal mucosa (Do not directly treat inflammation, but symptoms thereof) . They can be short acting (4 hours), intermediate acting: 8-10 hours) and long acting (12 hours)

They are typically administered as topical decongestants: Nasal sprays, gels and nasal drops. Inhalation of volatile compounds to achieve decongestion of the mucous membranes of the nose

• What is rhinitis medicamentosa?  How is it treated?

Rhinitis medicamentosa (RM) is a condition induced by overuse of nasal decongestants. This overuse can cause sustained vasoconstriction of the nasal blood vessels which leads to leading to the continuing of poor blood supply to the nasal mucosa. Treatment includes 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 have multipotent effects and not only blocks H1 receptors, but also muscarinic receptors. This antagonism can cause reduction of mucus secretion in the airways because of this, they are usually used in cold preparations in rhinohorrea. They do possess sedative effects and can thus decrease concentration.

Second gen are not multipotent and only antagonise H1 receptors which means mucus production will not be decreased. They are, however, useful in long-term or short-term treatment of allergic rhinitis and  they do not possess sedative effects. Because histamine plays no part in cold rhinitis (but bradykinin does) these drugs do not help to clear up cold rhinitis.

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

Corticosteroids (nasal sprays) for clinical use for allergic rhinitis can be administered topically (nasal spray) or systemically (orally)

Anti-allergic drugs: nasal spray is very effective for the prophylactic treatment of allergic rhinitis, but the regular dosage makes it less popular

Mesna: Topical mesna (nasal spray) is especially meaningful to use when the nasal secretion is sticky.  The mesna helps to make the mucus more liquid.

Normal salt solution: It humidifies the dry, inflamed mucous membranes of the nose during colds, dry weather, allergy (hay fever), nose bleeding, overuse of decongestants and other irritations. It is administered  as nose drops.

Give your own definition of COPD:

COPD refers to a variety of combinations of different diseases that cause airflow blockage (limit pulmonary airflow) and gas exchange this causes a difficulty in breathing. These different diseases are: Bronchial asthma, chronic bronchitis and emphysema. 

Briefly describe the proposed aetiology and pathophysiology of chronic bronchitis and emphysema:

Chronic bronchitis:
Non-specific COPD. The cause of chronic bronchitis is usually long-term exposure to irritants such as cigarette smoke. Chronic bronchitis is thought to be caused by overproduction and hypersecretion of mucus by goblet cells and the decrease in mucus clearance . Epithelial cells lining the airway respond to toxic, infectious stimuli by releasing inflammatory mediators and eg pro-inflammatory cytokines. Regular respiratory bacterial infections occur due to the increased mucus which promotes the growth of bacteria. Structural changes to the bronchial walls also takes place since airways get tight, swollen and filled with mucus. Due to this thick mucus, chronic cough manifests. 

Emphysema:
Disease that is caused by long term exposure to airborne irritants, the most common being inhaled smoke. It is characterised by the irreversible dilation of respiratory bronchioles and alveoli due to structural damage. Expiration is proven to be difficult due to air being trapped in the lungs (no way for new air to come in) The capillary blood vessels which surrounds the alveoli delays gaseous exchange which results in a build up of CO2. This can lead to hypoxic conditions. 

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

Smoking cessation: 
Prevents progression of disease. Psychotherapy, consultation, encouragement and support can help the patient to stop their smoking habit. (Drugs containing nicotine should be avoided for a period of time)

Bacterial infection: 
Influenza immunization which prevents secondary infections.
Broad spectrum antibiotics.

Obstruction of airflow:
Bronchodilators, M-antagonists are usually first line in COPD (tiotropium and ipratropium), Beta-2 agonists can also be used as well as theophylline. If unsuccessful, corticosteroids can also be administered. 

Mucus secretions:
Dilute mucus with rehydration and steam

Hypoxia: 
oxygen inhalation 

Poor lung capacity:
Light to moderate exercise. 

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

Chronic bronchitis is usually associated with increased parasympathetic nervous system activity. Since Ipratropium is an anticholinergic drug, this activity will be blocked. A reduction in bronchospasm caused by parasympathetic activity will be observed. (bronchodilation)

Bronchial asthma is mostly caused by inflammatory messengers which cause inflammation in the lungs and is followed by bronchospasm. Ipratropium can still relieve bronchoconstriction, but not as effectively. 

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

Theophylline strengthens the contraction of the diaphragm skeletal muscles which improves the ventilation response and reduces hypoxia and dyspnea in COPD patients. 

What is the role of oxygen therapy in COPD?

Oxygen is used to treat hypoxic conditions caused by impaired gaseous exchange found in COPD. This therapy increases oxygen in your lungs and bloodstream- more oxygen in capillaries of the lungs, therefore more oxygen can be provided to the body. 

Give a short and critical explanation of the rationale of using fluvoxamine (a selective serotonin reuptake inhibitor (SSRI) in the treatment of Covid patients:

Fluvoxamine has a high affinity for the S1R (ER-resident protein sigma-1-receptor). This receptor is responsible for the restriction of endonuclease activity of the Endoplasmic reticulum stress sensor, IRE1. It also restricts cytokine expression. Fluvoxamine does not, however inhibit inflammatory signaling pathways.The cytokine expression acts as an inflammation-causing symptom in COVID-19. With this, Fluvoxamine dampens the inflammatory response in human blood leukocytes. (CIDRAP, 2021)

Therefore, fluvoxamine is being researched as a treatment method for the Covid-19 virus. 

Reference: 

CIDRAP (Center fro Infectious Disease Research and Policy). 2021. OCD drug spotlighted as potential COVID-19 treatment. https://www.cidrap.umn.edu/news-perspective/2021/04/ocd-drug-spotlighted-potential-covid-19-treatmentDate of access: 16 Oct. 2021. 

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

Vasodilation caused by substances that induce vasodilation and originate from the endothelium (also synthesised from endothelium. Different stimuli that are found in endothelial cells causes NO synthesis (ex: increased cellular calcium etc) NO causes vasodilation. Thus it can be an endothelium-dependent vasodilator. 

• 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 synthesised at a constant level. (Produced in constant amounts regardless of substrate concentration) 
Inducible enzymes are enzymes that is synthesised only when they add adaptive value-or when exposed to a substrate. 

Because constitutive enzymes are more constant-and therefore always present the chances of them being affected by pathology is higher than that of inducible enzymes that are temporary. 

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

Many substances (endotoxins, cytokines, TNF-alpha) that are released by sepsis lead to the synthesis of iNOS located in macrophages, smooth muscle etc. This can lead to excessive production of NO which can lead to severe hypotension and shock associated with sepsis. 

• 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?

Scavengers of superoxide anion such as superoxide dismutase may protect NO, enhancing its potency and prolonging its duration of action. Nitrate tolerance.

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

NO that is released not only causes vasodilation, but due to its role in prostaglandin synthesis in the COX2 pathway, it results in an inflammatory response. This contributes to erythema, vascular permeability and oedema associated with acute inflammation. 

Disadvantageous: Excessive secretion of NO can worsen tissue injury and have an influence on disease pathology. 

Advantageous: NO that is produced inflammation, along with peroxynitrite that forms from its interaction with superoxide, is an important microbicide. NO also appears to play an important protective role in the body via immune cell function.

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

Parkinson’s disease, stroke.

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

Angiotensinogen is increased in hypertension and heart failure

Implications: an increase in angiotensinogen leads to a build up of angiotensin I that is converted into angiotensin II, thus decreasing the amount of bradykinin in the body causing vasoconstriction. Which leads to raised blood pressure levels as well as urinary retention. 

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

Angiotensin antagonists selectively block the angiotensinogen system  which means that less negative effects are elicited by these drugs. Whereas ACE inhibitors are non-selective and have extra effects such as a dry cough and angioedema.

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

These inhibitors inhibit the conversion of  Angiotensin I to Angiotensin II, which will lead to a decrease in Angiotensin II production resulting in a decrease in RAAS. This decrease will mean that bradykinin can't be broken down to a metabolite, therefore it will remain a potent vasodilator =. 

A decrease in peripheral vascular resistance will follow which leads to a decrease in 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?

Losartan is an angiotensin II receptor antagonist  (Inhibit angiotensin  AT1 receptors in heart, blood vessels, kidneys and brain) They fully block the angiotensin system (similar to ACE inhibitors but there isn't an increase in bradykinin
 

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 which increase in capillary permeability. Other autocoids do play a role in this action, but they act as second messengers such as Nitric Oxide (released after bradykinin activation)

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

Bradykinin 2 (B2) receptor

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

Natriuretic peptides are vasodilators, which means there will be a decrease in peripheral resistance and cardiac output which leads to a decrease in 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.

Neprylisine is an enzyme that metabolises ANB and BNP.  If the activity it inhibited, the effects of ANP and BNP are prolonged which leads to vasodilation and the decrease of peripheral resistance and heart output. This leads to natriuresis and diuresis.

The drug used is Sacubitril. It can be used in combination with Valsartan which is an ACE inhibitor resulting in arterial vasodilation. The combination is used for Heart Failure. 

Give examples of endothelium-derived vasodilators and vasoconstrictors. 

vasodilators: PGI₂ & NO

vasoconstrictors: Endothelin - ET₁, ET₂, ET₃

Pathology of migraine 

Migraine is known to be a throbbing unilateral headache that can last for a few hours or even 1-2 days. It is characterised by an aura which can involve nausea, vomiting, visual scotomas or even hemianopsia and speech abnormalities. The headache follows. 

The trigeminal nerve distribution to intracranial arteries is involved in migraine. Peptide neurotransmitters, especially calcitonin gene-related peptide, are released by these nerves. CGRP is a powerful vasodilator. Leakage of plasma and plasma proteins into the perivascular space causes mechanical stretching which may immediately activate the pain nerve endings in the dura. 

Treatments:

5-HT1D/1B agonists, aka triptans such as sumatriptan are almost exclusively used for the treatment of migraine. These drugs activate the 5-HT1D/1B receptors which are found on the presynaptic trigeminal nerve endings in order to inhibit vasodilating peptides. This will cause vasoconstriction which may prevent the stretching of pain endings. (Used in acute severe attacks) 

Ergot alkaloids: Ergotamine and Ergonovine can be used in the treatment of migraine. These drugs act as mixed partial agonists at 5-HT₂ and alpha adrenergic receptors. When used in treatment for migraine it has a similar mechanism of action as triptans.

Beta-adrenoceptor blockers: are effective only for prophylaxis and not for the acute attack

Calcium channel blockers: Prophylaxis

Nonsteroidal anti-inflammatory analgesic agents can be used to treat the pain.