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

Cytsic fibrosis is an inherited disease that affects the lungs, digestive system and sweat glands. Dornase alfa acts like scissors by cutting up the long DNA strands contained in WBCs. By cutting these strands into shorter pieces, dornase alpha helps break up thick, sticky mucus that often leads to lung infections.

• 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 a breathing disorder in newborns caused by immature lungs. Corticosteroid are given prophylactically to the mother before labour to initiate baby's surfacant production.

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

Babies with heart or lung problems may need to breathe increased amounts of oxygen to get normal levels of oxygen in their blood. Oxygen therapy provides babies with extra oxygen.

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 is a pause in breathing that lasts 20 seconds or longer in infants.  A pause in breathing lasts less than 20 seconds and makes the baby's heart beat more slowly (bradycardia).

Methylxanthines block the phosphodiesterase enzyme , which results in relaxation of smooth muscle in the lungs, dilation of pulmonary blood vessels, elimination of excess fluid through diuresis, and stimulation of the central nervous system.

Caffeine and Theophylline are used.

• 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.

alpha- agonists - oxymetazoline

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?

2^nd 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 (applied to body surface; skin)

• Give your own definition of COPD.

A pulmonary disorder that occurs as a result of increased airway resistance or of decreased elastic recoil.

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

Chronic bronchitis: Aetiology

Chronic bronchitis is caused most often by exposure to airborne pollutants such as cigarette smoke, excessive dust in the air or chemicals. The bronchial lining becomes inflamed and the constant exposure to such pollutants begins to cause damge in the bronchioles.

Pathophysiology:

Chronic bronchitis is thought to be caused by overproduction and hypersecretion of mucus by goblet cells. Epithelial cells lining the airway response to toxic, infectious stimuli by releasing inflammatory mediators and pro inflammatory cytokines.

Emphysema: Etiology

The cause of emphysema is usually long-term exposure to irritants that damage your lungs and the airways. Tobacco smoke can also cause emphysema, especially if you inhale them.

Pathophysiology:

is pathologic diagnosis defined by permanent enlargement of airspaces distal to the terminal bronchioles. This leads to a decrease in the alveolar surface area available for gas exchange. Furthermore, loss of alveoli leads to airflow limitation.

 

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

Smoking cessation; Immunization against influenza; Bronchodilators; Oxygen inhalation: Rehydration and steaming

 

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

Ipatropium is an M3 antagonist. It reduces bronchoconstriction this results in decreased secretions. However with bronchial asthma increased secretions does not give the same effects.

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

Theophylline improves contraction function of the diaphragm. It works by relaxing the muscles in the lungs and chest, since COPD is characterized by airway resistance.

• What is the role of oxygen therapy in COPD?

Oxygen treatment increases the amount of oxygen that flows into the lungs and bloodstream. If  COPD is severe and  blood oxygen levels are low, getting more oxygen can help breathe better.

• Which vascular changes can be observed before and during migraines?

Vasodilatation

• What is the role of serotonin in migraine headaches?

Serotonin vasoconstricts the nerve endings and blood vessels and affects nociceptive pain.

• How is ergotamine used during a migraine attack?

It is a 5HT1_D  partial antagonist of intracranial arteries and inhibits trigeminal nerve transmission. It should be used at first sign of migraine.

• Which side-effects are experienced with ergotamine use? Which contra‑indications exist for using ergotamine?

Side effects: Nausea, Vomiting, diarrhoea, hallucinations, gangrene.

Contra-indictaions: Pregnancy, hypertension, liver and kidney impairment.

• Which other drugs can be used for an acute migraine attack?  What is the action of all of these drugs?

Aspirin, Paracetamol, Metoclopramide, Cyclizine , Sumatriptan

• Name the drugs which can be used for migraine prophylaxis, as well as their specific side effects and precautions

Drugs used for migraine prophylaxis: Propranolol, Clonidine, Verapamil, Valproic acid, Pizotifen.

Side effects: Drowsiness, Fatigue, Weight gain

 

 

• What is the mechanism of action of colchicine in the treatment of gouty arthritis?

Colchicine is a selective inhibitor of microtubuli and spindle formation in macrophages  and leukocytes. It also inhibits chemotaxis.

• 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.

Indication: Acute gout (in patients intolerant to NSAIDS)

Side Effects: gastric bleeding, liver/kidney damage, bone marrow suppression, alopecia.

Dose: 0.5 - 1 mg

• Which other drugs can be used for the treatment of an acute gout attack?

NSAIDS( Diclofenac, Piroxicam, Indomethacin), Glucocorticoids( Prednisone, Betamethasone)

• To which group of drugs does probenecid belong?  How does this group of drugs act?

It is a uricosuric drug; It increases excretion of uric acid by competing with uric acid for reabsorption in proximal tubule in kidney.

• How does allopurinol act; what are its indications, precautions and important interactions

Mechanism of action: Irreversible inhibitors of xanthine oxidase, decreases uric acid production

Indications: Chronic gout

Precautions:  increases [xanthine] and [hypoxanthine], avoid in acute gout attack. Can induce acute gout (use with NSAIDs)

 

 

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

Paracetamol has analgesic effects mediated through activation of descending serotonergic pathways. It inhibits prostaglandin synthesis by reducing the active form of 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.

• 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 pains such as headaches, toothache, sprains and colds and flu.

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

nausea, stomach pain, jaundice, dark urine and loss of appetite.

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

Paracetamol toxicity is caused by excessive use of paracetamol. It occurs during a period of up to 8 hours after ingestion. The symptoms are abdominal pain, irritability, loss of appetite, diarrhea, vomiting, nausea. Paracetamol toxicity is treated by N-acetyl-cysteine(NAC). 

 

 

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that is approved by the Food and Drug Administration (FDA) for the treatment of obsessive-compulsive disorder and depression. Fluvoxamine is not FDA-approved for the treatment of any infection.

Fluvoxamine was discovered to bind to sigma-1 receptors which results in reduced production of inflammatory cytokines and inflammatory genes.

There is insufficient evidence for the COVID-19 Treatment Guidelines Panel to recommend either for or against the use of fluvoxamine for the treatment of COVID-19

 

SOURCE: https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/

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

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

• 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 - an enzyme that is formed at a constant rate and in an constant amount in a given cell.

Inducible - is an enzyme that is normally present in minute quantities within a cell but whose concentration increases dramatically when a substrate compound is added. 

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

Nitric Oxide synthesis is dysregulated exaggerated production leading to cardiovascular dysfunction, bioenergetic failure and cellular toxicity

Excessive formation of NO is a major factor involved in the pathologic vasodilatation and tissue damage observed.

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

NO - Nitric Oxide.

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

It can be inactivated by reacting with O₂ (Oxygen) to form nitrogen dioxide. It also reacts hemoproteins which oxidize NO to Nitrates.

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

It is considered a proinflammatory mediator because it induces inflammation due to overproduction in abnormal situations.

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

Parkiinson disease and stroke

 

 

 

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

Hypertension, angiotensin synthesis is stimulated by estrogens, angiotensin II, thyroid hormone and glucocorticoids. Increased  levels of angiotensin can cause the body to retain too much fluid or to have elevated blood pressure levels. High angiotensin levels can also 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?

ACE inhibitors lower blood pressure by preventing the production of angiotensin II while angiotensin receptor blockers reduce the action of angiotensin  to prevent blood vessel constriction. Angiotensin receptor blockers give a bigger decrease in cardiovascular effects than ACE inhibitors especially in patients with cardiovascular diseases.

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

ACE inhibitors inhibit the synthesis of Angiotensin II by stimulating the dilation of blood vessels. They inhibit the breakdown of bradykinin to an active metabolite which decreases 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?

AT₁ receptors , they  have indirect effects on angiotensin II receptors

• 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.

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

Beta 1 and Beta 2 receptors.

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

They are vasodilators. ANP is released in atria after tension on heart ventricles.

• 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.

Inhibition of neprilysine blocks angiotensin II type-1-receptor, increasing the levels of peptide degraded by neprilysine. Neprilysine has a biological function of metabolizing ANP and clearing it from circulation. Sacubitril & Valsartan.

• Give examples of endothelium-derived vasodilators and vasoconstrictors. 

Endothelium-derived vasodilators: Nitric Oxide (NO) and Prostacyclin (PG1₂)

Endothelium-derived vasoconstrictors:  Thromboxane(TXA₂₎ and Endothelin-1 (ET-1).

 

 

 

 

 

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

Pathophysiology: Migraine is caused by the dilation and inflammation of cephalic arteries and intracranial extra cerebral arteries.

Drugs used for migraine:

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

Serotonin also plays a role in migraine, specifically 5HT1_D agonists such as Sumatriptan, Naratriptan and Rizatriptan. They increase intracranial vasoconstriction and counteracts vasodilatation that causes pain in migraine

Ergot alkaloids may also be used for the treatment of migraine (acute) since they are partial agonists at both serotonin and alpha receptors.

Other drugs such as ibuprofen can be used to treat migraines (anti-inflammatory drugs)