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 - a breathing disorder in new-borns caused by immature lungs.

General treatments - Oxygen. &.  Ventilator.

Exogenous surfactant. It eventually promotes gaseous exchange. It is regarded as a therapeutic option for new-borns, children, and adults to improve surfactant.

Corticosteroids. It initiates baby’s surfactant production. It is administered to child/new-born and to the mother before birth.

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

Oxygen therapy is just to increase the blood oxygen levels of the baby to prevent hypoxia. Too much oxygen can damage the retina of the baby and can even lead to blindness.

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

neonatal apnoea is caused by incomplete development of the respiratory centre within the brain, leading to incomplete continuous stimulation of breathing. Thus, the baby repeatedly stops breathing and has a slowing of heartbeat for 15 seconds or longer.

Theophylline is Methylxanthines used which works by relaxes smooth muscles, including those of the bronchi, oesophagus, and gastroesophageal sphincter. They can reduce fatigue and improve concentration.

What are the general causes of rhinitis and rhinorrhoea?

Allergy, 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

Decongestants

 Alpha1-agonists – phenylephrine

    Antihistaminic and antimuscarinic drugs - Brompheniramine

    Corticosteroids – Betamethasone

Anti-infective drugs

    Anti-allergy drugs – Sodium cromoglycate

    Mucolytics – Mesna

   Diverse Drugs – Normal salt solutions and volatile oils

    Mast cell stabilisers- Ketotifen.

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

Oral decongestants – contracts nasal passages by activating post junctional alpha-adrenergic receptors

Topical decongestants - work by constricting the blood vessels within the nasal cavity.

Short acting drugs have a duration of 4 to 6 hours

intermediate acting drugs have a 8 to 10 hour duration

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?

Effectiveness of the first generation of antihistamines is due to their actions on histaminic and muscarinic receptors in the medulla. Second generation antihistamines do not cross the blood-brain barrier. Advantages of the second generation of antihistamines is that they lack sedation and impairment of performance, have a longer duration of action and do not have anticholinergic side effects. They should not be used to relieve cold rhinitis because histamine levels are not elevated in nasal secretions of people with a cold.

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

Corticosteroid nasal sprays use with caution in infection-induced conditions, this is due to increased systemic uptake. It is administered via the nasal route.

Anti-allergic drugs are used in treatment of allergen-induced rhinitis or/and rhinorrhoea. It is administered via the oral or parenteral route.

Mesna is regarded as a chemoprotective and anti-neoplastic drug. It reduces toxicity in urinary passages. It is adverse reactions includes respiratory disorders such as nasal congestion, cough, dry mouth, bronchoconstriction, etc. It is administered parenterally (intravenous injection).

Normal salt solutions are used to dilute mucus and are administered nasally.

1.Give your own definition of COPD.

A conditioned caused by bronchial asthma, chronic bronchitis, and emphysema. It is related to the lungs and lead to blockage of airways, thus causing difficulty in breathing.

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

Chronic bronchitis

Aetiology -bronchial lining becomes inflamed and the constant exposure begins to cause damage in the bronchioles. exposure to includes cigarettes smoke, excessive dust in the air, or chemicals.

Pathophysiology - increase of mucous secretion and a decrease in mucosal clearance. Airways become narrowed and limit airflow in and out of the lungs.

Emphysema

Aetiology - cigarette smoke is the main cause. Pipe, cigar, and other types of tobacco smoke.

Pathophysiology - the inner walls of the lungs' air sacs (alveoli) are damaged, causing them to eventually rupture.

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

• Smoking cessation.
• immunisation.
• Bronchodilators.
• Rehydration and steaming.
• Oxygen inhalation.
• Light-moderate exercise
• Surgery, lung transplant.

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

Ipratropium - an antagonist of the muscarinic acetylcholine receptors

It stops or reduces bronchoconstriction, mucous secretion and bronchial vasodilation that result from vagal stimulation of the airways. It is a reliever in bronchial asthma, but it relaxes and opens the air passages in the lungs in chronic bronchitis.

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

It causes smooth muscle relaxation, thus inducing bronchodilation. Bronchodilation allows for easier airflow due to expansion of the bronchial air passages. This improves breathing.

6.What is the role of oxygen therapy in COPD?

increases the amount of oxygen that flows into the lungs and It is used for treating hypoxia.

Fluvoxamine (selective serotonin reuptake inhibitor) binds to the sigma-1 receptor in immune cells, resulting in reduced production of inflammatory cytokines and inflammatory genes. From The Medical letter published on the 3^rd of May 2021, sigma-1 agonism inhibits SARS-CoV-2 replication. fluvoxamine theoretically prevents the development of life-threatening cytokine storm and acute respiratory distress syndrome in coronavirus COVID-19.

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

This is done by increasing shear stress on the endothelium. increase in blood flow stimulates endothelium-dependent vasodilation

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

• eNos and nNOS are both constitutive enzymes. Both need to be activated. Activation occurs when NO synthesis is triggered by agents which then increases cytosolic calcium concentrations. The cytosolic calcium forms complexes with calmodulin which then binds and activates these two enzymes. Thus they are calcium dependant and readily detectable and release from various cell types
• iNOS is an inducible enzyme, meaning it’s not regulated by calcium, but is active after synthesis.It is not readily detectable until inflammatory mediators induce the transcription of the iNOS gene – resulting in its accumulation and large quantities of NO. It is calcium independent and released from smooth muscle and Macrophages.

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

• Septic shock is a life-threatening condition caused by sever localised or wide spread infection that requires medical attention. Sepsis usually means that the infection has spread into the blood stream and is now affecting every organ within the body.
• Sepsis is an inflammatory response due to a serious infection. The infection usually triggers cytokines to release iNOS in macrophages, neutrophils, and T-cells, as well as hepatocytes, smooth muscle cells , endothelial cells and fibroblasts.
• The widespread release of NO leads to exaggerated Hypotension, shock and in extreme cases – death. NO is a potent vasodilator, thus the exaggerated vasodilation would have lead to exaggerated hypotension

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

Nitric oxide. Nitric oxide activated the conversion of guanylyl cyclase to activated guanylyl cyclase, this will eventually lead to the conversion of GTP to cGMP. The elevation of cGMP will lead to vasodilation and relaxation of smooth muscle.

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

Arginase is an enzyme in the urea cycle that hydrolyses L-arginine to urea and L-ornithine. It suppresses nitric oxide.

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

• During the infection there is An increase in iNOS levels. No has a pro-inflammatory effect in the TH1 cell function and by stimulating the synthesis of inflammatory  prostaglandins by activiating COX2
• Advantages are its direct vasodilatory effects and other mechanisms that lead to erythema, vascular permeability and subsequent edema.
• Disadvantages lie in long term effects due to chronic inflammation such as exacerbation of tissue injury such as psoriasis lesions, airway epithelium in asthma and inflammatory bowel lesions. It May also exacerbate arthritis.

In which possible neurological and psychiatric diseases is NO involved? 

physiological functions such as noradrenaline and dopamine releases

diseases: schizophrenia, bipolar disorder

1. In what disease states were angiotensinogen levels elevated? What are the effects of this?

hypertension. angiotensin synthesis is stimulated by estrogens, angiotensin II, thyroid hormone and glucocorticoid. thus the elevation of angiotensinogen will lead to more glucocorticoids, thyroid hormone, estrogens, and angiotensin II.

Increased  levels of angiotensin can cause the body to retain too much fluid by the release of aldosterone and ADH or to have elevated blood pressure level

2. What is the reason why drugs that inhibit the angiotensin system by acting on angiotensin receptors have fewer side effects than those that inhibit ECPs?

 ACE inhibitors blocks the breakdown of kinin, Increased level of kinin is responsible for these side effect; Dry cough increased potassium levels in the blood (hyperkalaemia),Fatigue ,Dizziness from blood pressure going too low,Headaches

ARBs specifically bind to AT receptors

3. How do ACE inhibitors have a dual mechanism of action in treating high blood pressure?

 Relaxes arteries and blood vessels by vasodilation. It works by blocking angiotensin II receptors, which are caused by vasoconstriction in blood vessels. Interferes with the body's RAIS. This also regulates the blood pressure of the body.

4.What types of angiotensin receptors do losartan and similar drugs work on? Do they have direct or indirect effects on other angiotensin II receptors?

Losartan is an angiotensin II antagonist that acts on AT1 receptors. Long-term use of the medication can stimulate AT2 receptors.

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

quinines are mediated by specific B1 and B2 receptors. Activation of quinine receptors is particularly important for the treatment of blood pressure regulation. Quinines are vasodilators. There are several autacoids that also play a role, e.g. Eg PGE2 and PGI1, phospholipase A2, chloride transport, etc. It acts as second messenger transducts. Endothelium-derived vasodilates

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

Kinins produce marked arteriolar direction in several vascular beds, including heart and skeletal muscle. The vasodilation may result from a direct inhibitory effect of kinins on arteriolar smooth muscle.  They maybe mediated by the release of NO, vasodilator prostaglandin such PGE₂ and PGI₂

7.which receptor is probably the most involved in the important clinical effects of kinins?

Kinin B2 receptors

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

The excretion of sodium(salt) and water decreases fluid volume, in turn decreasing blood pressure,  vasodilation allow for widening of blood vessels which facilities easier flow of blood, eventually reducing blood pressure.

9.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 inhibitors are used to treat high blood pressure and heart failure. They work by blocking the action of neprilysin thus preventing the breakdown of natriuretic peptides.Omapatrilat (including entresto and sacubitril/valsartan) is a neprilysin inhibitor, it decreases metabolism of natriuretic peptides and formation of angiotensin II, thus causing vasodilation and increased sodium and water excretion.

10.Give examples of endothelium-derived vasodilators and vasoconstrictors. 

endothelium-derived vasodilators. Bosentan, macitentan. Sitaxsentan, ambrisentan ad  Daglutril

Endothelium-derived vasoconstrictors

• Adrenalin        
• Thrombine      
• Angiotensin II            
• Vasopressinc
• Endotoxin (LPS)        
• Insuline
• Calcium ions

Migraine headache is a recurrent throbbing headache that typically affects one side of the head and is often accompanied by nausea and disturbed vision.

pathology of migraine it is caused by the dilation and inflammation of cephalic arteries and intracranial extra cerebral arteries.

Serotonin: Sumatriptan, Naratriptan, Busiproon, and Eltriptan, these medications increase intracranial vasodilation.They act as partial agonists for 5-HT1A, B, and D receptors.
Acute migraines are treated with these medications and they are first line of treatment.

Ergotamine and dihydroergotamine : Ergotamine is used to treat acute migraines and headaches.
It's a partial agonist for 5HT2, Alpha, and central dopamine receptors that's mixed.
These medications have a vasoselective effect.
Smooth muscle contraction and vasoconstriction are caused by this medication, which helps to relieve migraine symptoms

Calcium blockers and beta blockers : Propranolol reduces intensity and frequency of migraine. Metoprolol, Timolol and Atenolol also give the same efficacy

Verapamil: considered to have modest efficacy as prophylaxis against migraine