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

Cystic fibrosis is a genetic metabolic disease (decrease in DNase 1) in which secretion in the body are decreased and the body struggles to get rid of mucous as mucous production also increases. 

Dornase alpha hydrolyses enzymes hydrolyzed mucous to make it more fluid. 

2. 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 also known is hyalin membrane disease. It occurs in premature babies where the surfactants that cover the airways and essential for gaseous exchange only develop shortly before birth, lung fall and lead to death

Cortisone- betamethasone is given to the mother prophylactically before birth to initiate the baby’s surfactant production

Exogenous surfactant- boractant and poractant alpha to augment lung surfactant

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

To ensure oxygenation and prevent hypoxia

The toxicities are retinal damage and blindness

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

Neonatal apnoea occurs in premature and newborn babies where the respiratory centre in the brain isn’t fully developed yet to ensure continuous breathing. Bradycardia and apnoea last longer for 15 seconds and occur repeatedly. Lead to neural damage and hypoxia

Methylxanthines such as theophylline is administered by IV to stimulate the CNS to promote respiratory function and prevent hypoxia. 

What are the general causes of rhinitis and rhinorrhoea?
Pollen; overdose of local preparations; allergies( hay fever) and viral infections

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

antihistamines - Promethazine

Corticosteroids - Prednisone

Mast stabilisers - Ketotifen

Mucolytics - Mesna

Antibiotics - Mupirocin

Diverse drugs - normal saline

How do the decongestants differ with respect to the mechanism of action and duration of action?  How are they administered typically?
Decongestants activate alpha-adrenergic receptors of the nasal mucosa. They oppose vasodilation which causes vasoconstriction causing reduction in nasal airway resistance.

They are usually nasal sprays - through the nose.

What is rhinitis medicamentosa?  How is it treated?
Rhinitis medicamentosa is a condition caused by nasal decongestants

The first step to treating this condition is to stop using nasal sprays. Imidazoline can be used to treat it.

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?
2nd generation antihistamines do not block muscarinic receptors and are useful for long-term  treatment of allergic rhinitis.  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? 
For prophylactic allergic rhinitis. They are used topically which also minimizes side effects

Do you know any drugs/ groups of drugs that may cause cough as a side effect?

 Other medications induce cough by provoking bronchospasm (including beta blockers, NSAIDs, and aspirin-containing products) or by worsening gastroesophageal or laryngopharyngeal reflux (including bisphosphonates, calcium antagonists, and systemic steroids).

Give your own definition of COPD
COPD stands for chronic obstructive Pulmonary Disease. It is the different combination of bronchial asthma, emphysema, and chronic bronchitis to different degrees.

Briefly describe the proposed aetiology and pathophysiology of chronic bronchitis and emphysema.
Chronic Bronchitis: It is non-specific COPD characterised by: increased mucus secretion (mucus hypersecretion), decreased mucociliary clearance regular bacterial respiratory infections, structural changes in bronchial walls and a chronic cough due to thick mucus.

Emphysema: Often develops due to smoking and irritants. Emphysema is IRREVERSIBLE widening of respiratory bronchioles and alveoli, due to structural damage. The Damage cannot be reversed. Air is trapped in lungs which makes expiration difficult. The decreased capillary blood vessels impedes gaseous exchange.

Which types of therapy are included in the treatment of a COPD patient?
The types of therapy are: self-management, bronchodilators, inhaled corticosteroids, methylxanthines, oxygen and surgery.

Stop smoking:

Extremely important and is necessary to prevent progression. Psychotherapy, consultation, and encouragement (rather positive than cautionary), as well as support, possibly with other drugs, is important to wean the smoke
If bacterial infection

influenza immunization (prevents 2ndary infections)
broad spectrum antibiotics (tetracyclines, amoxicillin, ampicillin, erythromycin, co-trimoxazole)
Obstruction of airflow

Bronchodilators
Mucus secretions

Dilute mucus (rehydration & steam)
Rehydration (sufficient intake of liquids) & regular steaming (humidifier)
Hypoxia

Oxygen inhalation. The morbidity and mortality in serious grades of COPD improve drastically with 18-24 hours/day O2 inhalation therapy. It is therefore strongly recommended in cases of continued hypoxia (various types of portable O2 containers are available).  Some patients require O2 inhalation therapy only with exercise or during sleep
Poor lung capacity

Light/ moderate exercise
Why is ipratropium more effective in the treatment of chronic bronchitis than in the treatment of bronchial asthma?
Bronchial asthma is characterized by inflammation and Ipratropium does not have an anti-inflammatory effect and will thus not be as effective in treating bronchial asthma.

In which way do the skeletal muscle effects of theophylline have advantages in the treatment of COPD?
Skeletal Muscle effects: Strengthens contraction of diaphragm skeletal muscles. Improves ventilation response, reduces hypoxia and dyspnea in COPD patients.

What is the role of oxygen therapy in COPD?
If the combination of ipratropium, a b2-sympathomimetic and theophylline does not provide enough relief and the patient is unable to receive enough oxygen, oxygen therapy must be applied.

• What are the therapeutic effects of theophylline in the treatment of bronchial asthma?

• What are the primary mechanisms according to which the therapeutic effects are evoked? What is the mechanistic connection with b2-agonists and antimuscarinic drugs? How would you describe the interaction with the b2-agonists molecular-pharmacologically?

• On which other systems in the body do the methylxanthines have an effect?  Where do you see the potential for undesirable side-effects and possibly also for other therapeutic applications of these side-effects?  Place special emphasis on the central and skeletal muscle effects.

• What can you say about serious toxicities and the therapeutic index of theophylline?  How can the plasma levels of theophylline be influenced by pharmacokinetic drug interactions?  With which drugs can it be clinically important and why?

• How is theophylline administered?  What are the advantages of the slow-release forms? 

• You have a patient who uses theophylline for the treatment of chronic asthma.  Your patient, however, develops a cold leading to a worsening of asthma.  After a week your patient develops a secondary bacterial infection and the doctor prescribes a penicillin antibiotic.  You are an alert pharmacist and quickly detect that your patient is allergic to penicillin.  You phone the doctor who suggests that you must rather give erythromycin antibiotic.  Do you think it is a good idea?  Assume your patient has developed a genitor-urinary tract infection, do you think it is a good idea to use ciprofloxacin?  And if she has a problem with heartburn, are there drugs that you should be careful to recommend?  Make use of your SAMF in considering the case.
• No, because theophylline can help prevent anti inflammatory effects, but can affect renal. It can cause diuresis which could contraindication the patients health urinary tract infections. We should becareful to prescribe drugs such as propranolol, erythromycin, antifungal, antibiotics etc since these can can contraindicated his conditions. 

1.Which vascular changes can be observed before and during migraines?
Strong vasodilators cause vasodilation and oedema, which activate pain nerve endings. 

2.What is the role of serotonin in migraine headaches?
5-HT or serotonin receptors, agonists constrict the arteries which then inhibits trigeminal nerve transmission and vasoactive peptide release.

3.How is ergotamine used during a migraine attack?
Ergotamine is a partial 5-HT1 agonist which causes vasoconstriction in the intracranial arteries and inhibits trigeminal nerve transmission.

4.Which side-effects are experienced with ergotamine use? Which contra‑indications exist for using ergotamine?
Side effects include nausea, vomiting, diarrhoea, hallucinations, gangrene strong vasoconstriction, tachycardia and rebound headache. Contra-indications include cardiovascular disease, hypertension, patients suffering from liver and kidney impairment, pregnancy, and psychosis.

5.Which other drugs can be used for an acute migraine attack?  What is the action of all of these drugs?
Drugs that can be used for acute migraine attacks are Sumatriptan, Zolmitriptan, Almotriptan, Eletriptan, Naratriptan- These drugs are 5-HT1B/1D/1F agonists. They constrict the large arteries, inhibits trigeminal nerve transmission and vasoactive peptide release.

Metoclopramide-Anti-emetic, D2 antagonist at the chemoreceptor trigger zone in CNS

Cyclizine-Anti-emetic, First-generation ant-histamine, competitive antagonist at H1, muscarinic, alpha and 5-Ht receptors.

6.Name the drugs which can be used for migraine prophylaxis, as well as their specific side effects and precautions
Beta-blockers and alpha 2 agonists can be used as migraine prophylaxis. Propranolol(B-blocker) helps to stop a migraine but should not be taken during a migraine. Clonidine (alpha-2 agonist) causes vasodilation before initial vasoconstriction, but caution should be taken as it could induce a migraine attack. Calcium channel blocker-drugs could also be used such as Verapamil, Flunarizine (could prevent often attacks of migraines, Blocks H1) and Diltiazem. These drugs cause vasodilation after initial vasoconstriction. Side effects when taking Flunarizine include weight gain and depression. 

1.What is the mechanism of action of colchicine in the treatment of gouty arthritis?
When Colchicine is administered it binds to the intracellular protein tubulin, inhibiting polymerization into microtubules which then prevents leukocyte migration and phagocytosis. By preventing the migration of leukocytes to the side of inflammation, ingestion of urate crystals and release if more inflammatory mediators will not occur. Colchicine also inhibits the formation of leukotriene B4 and IL-1β thus preventing inflammatory effects 

2.What are the indications for colchicine’s use, its side effects and dose? Especially ensure that you know precisely how colchicine must be used during an acute gout attack.
Colchicine is used to treat gout and in between gout attacks. Side effects are diarrhea, nausea and vomiting. 

3.Which other drugs can be used for the treatment of an acute gout attack?
Other drugs include NSAIDs such as Indomethacin, Diclofenac, Piroxicam.

4.To which group of drugs does probenecid belong?  How does this group of drugs act?
Probenecid is used for chronic gout and falls under uricosuric drugs. These drugs compete with uric acid for reabsorption in the proximal tubule located in the kidney.

5.How does allopurinol act; what are its indications, precautions and important interactions?
Allopurinol inhibits Xanthine oxidase which then prevents Xanthine from forming uric acid in the body. This drug is used for chronic gout. Allopurinol can induce acute gout if not taken with NSAIDs. A caution to be taken is to be aware of the increased effects of cyclophosphamide which inhibits the metabolism of probenecid and oral anticoagulants which increases iron concentration.

Colchicine or NSAIDs are given initially with Allopurinol to help prevent gouty arthritis.

MOA: Irreversible inhibitors of Xanthine oxidase, which decreases uric acid production.

Indications: Chronic gout

Precautions: Use as prescribed by doctor. Do not use more than indicated, do not use longer than indicated. This will increase the side effects. Use after meals to prevent stomach problems. Do not use when all symptoms of gout attack is gone. Do not use with NSAIDs and patients with impaired renal function should avoid it.

Important Interactions: azathioprine, benazepril, captopril, didanosine, dyphylline, enalapril, perindopril, protamine.

1.What is paracetamol’s mechanism of action?  How does it differ from that of aspirin

Paracetamol has analgesic effects which is mediated through activation of descending serotonergic pathways, that inhibits prostaglandin synthesis by reducing COX1&2 enzymes.

Aspirin on the other hand is a non-selective and irreversibly inhibits both COX1&2,  it does so by acetylating the hydroxyl of a serine residue.

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

Indications: Migraine, toothache, colds, rheumatic pain and backache. Mild or moderate pains such as headaches, toothache, sprains, colds and flu.

3.Name side-effects that can occur with paracetamol use.

Skin rash, urticaria, nausea, jaundice, dark urine and loss of appetite.

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

Paracetamol toxicity is caused by over-excessive use of paracetamol. Toxicity can occur during a period of up to 8 hours after ingestion. The symptoms are abdominal pain, irritability, loss of appetite, diarrhea, vomiting, nausea. N-acetyl-cysteine can be used to decrease paracetamol toxicity. 

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 is a particular serotonin reuptake inhibitor that is used for the treatment of obsessive-compulsive disorder and is used for different conditions like depression. Fluvoxamine isn't FDA-supported for the treatment of any infection.

In a murine sepsis model, fluvoxamine was found to bind to the sigma-1 receptor in immune cells, resulting in a decrease in the production of inflammatory cytokines. In an in vitro study of human endothelial cells and macrophages, fluvoxamine decreased the expression of inflammatory genes. More examinations are needed and expected to establish whether the anti-inflammatory effects of fluvoxamine observed in nonclinical studies also occur in humans beings and are clinically applicatble in the treatment of covid 19 in patients. However, more research and tests have to be done to promote Healthcare, efficacy and safety. 

1.What do you understand by the term “endothelium-dependent” vasodilation?  Explain
Vasodilation is caused  by vasodilators that originate from the endothelium and are synthesised there. Endothelium-dependent vasodilators such as Acetylcholine and bradykinin increase the intracellular calcium levels in the endothelium leading to the synthesis of NO an endothelial-derived relaxing factor in the endothelium. NO moves to the vascular smooth muscle to cause its vaso-relaxing effect.

2.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 constantly being synthesized regardless of physiological need, resulting in greater physiological and pathological importance. Induced enzymes are enzymes that appear after a substance has been added, so the enzyme is present before the substance, which means the body has to excrete something before the enzyme works, so the effects are small. Endogenous substances may also interact with constitutive enzymes more often due to their more permanent presence in cells than inducible enzymes. Constitutive NOS will have greater pathological and physiological implications than inducible NOS.

3.Explain how NO contributes to the fatal pathology of septic shock.
Sepsis is a systemic inflammatory response caused by infection. Components present on bacteria such as endotoxins, cytokines and tumour necrosis factor-α induce the formation of iNOS in macrophages, smooth muscle cells, neutrophils. This NO formation in a wide area leads to severe hypotension, shock and in some cases death.

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

5.NO may be toxic to the cell.  Which mechanisms are available to the body to counter this detrimental effect of NO?
Haemoglobin can react with NO in the body and oxidize it to nitrate, thereby deactivating it. NO can also be deactivated by reacting with O2 in the body to form NO2. NO also rapidly reacts with metals in the body which also deactivate it and thereby counteract its detrimental effect on cells. The body releases NOS enzyme inhibitors which bind competitively to arginine binding site in NOS therefore arginine is not converted to nitric oxide.

6.Name a way in which NO can act pro-inflammatory.  Give examples of where it will have advantages or disadvantages.
The response to injury or infection leads to the activation of leukocytes and the release of inflammatory mediators, resulting in an increase in iNOS levels and activity in leukocytes. The NO and peroxynitrates produced are an important microbial agent. Function of the immune cell TH1, which synthesizes NO in response to an unknown substance. This is a good protective response, especially when iNOS is inhibited. NO also stimulates prostaglandin synthesis. The vasodilator effects of NO and the effects of COX2 play a role in inflammation, where it causes red skin color, increases vascular permeability and increases edema in acute inflammations. A disadvantage of NO in acute and chronic inflammation is that excessive NO production can lead to tissue damage, psoriasis lesions, airway epithelium in asthma and inflammatory bowel lesions.

7.In which possible neurological and psychiatric diseases is NO involved?
Myotrophic lateral sclerosis, Parkinson Disease and stroke.