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

Cystic fibrosis is genetic metabolic disease (↓ DNase 1, not have enough lead to decreased secretions in various organs especially airways) which leads to decreased secretions in various organs. Dornase alfa (rhDNase I) hydrolyses extra-cellular DNA from the neutrophils in the bronchial mucus, increasing its liquidity drastically. It is related to the natural enzyme deoxyribonuclease I (DNase I) which is normally produced by the pancreas and salivary glands. Hydrolyses proteins in bronchial mucus to improve fluidity

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

Also known as hyaline membrane disease, occurs in premature babies. Surface active agent (surfactant, which covers airways and is essential for gaseous exchange), is only formed shortly before birth, disrupted gas exchange, lungs may therefore collapse and can result in death. The surfactants are administered exogenously at room temperature (by means of a catheter into the lungs), prophylactically, or during acute respiratory distress syndrome to the neonate to augment lung surfactant. Eventually, the mortality and long-term oxygen requirement are lowered.

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

Oxygen (mixed with air at room temperature) is administered in order to ensure oxygenation. A continuous positive pressure (as obtained with a ventilator) improves respiration and keeps the alveoli open to prevent collapse. It is critically important that the arterial partial oxygen pressure is continuously monitored. Sufficient oxygen is a basic requirement for normal respiration. Therapeutically it is administered generally to prevent or reverse hypoxia (of various causes)

BUT increased oxygen for long-term leads to retinal damage and blindness. When oxygen is inhaled in excessive quantities and/or over too long a period of time, it has toxic effects. Paradoxically, oxygen toxicity causes, inter alia, reduced gas exchange, hypoxia and, in extreme cases, death. In neonates it can cause retinal damage and blindness.

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

New-born and premature babies: Respiratory centre in brain not yet fully developed to stimulate continuous breathing. Apnoea with bradycardia lasts longer than 15 seconds and occurs repeatedly. May lead to hypoxia and neural damage. Methylxanthine is used to stimulate the CNS, theophylline IV for few weeks is used as well as caffeine.

What are the general causes of rhinitis and rhinorrhoea?

Allergic rhinitis = allergen exposure, IgE mediated inflammation.
Non-allergic rhinitis = physiological response due to stimuli such as heat, smoke, cold.

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

Decongestants (alpha-agonists): oxymetazoline, xylometazoline, ephedrine

Antihistamines: diphenhydramine, loratadine, cetirizine 

Corticosteroids: betamethasone, prednisone, beclomethasone

Mast cell stabilizers: Sodium chromoglycate, ketotifen

Mucolytics: Mesna, acetylcysteine

Antibiotics: Mupirocin, neomycin

Diverse drugs: steam, normal saline, essential oils

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

Sympathomimetic agents, α1 agonists: vasoconstriction of mucosal blood vessels, ↓ oedema of nasal mucosa. Ephedrine, pseudoephedrine and propylhexedrine are nonselective adrenergic agonists (a and b) with additional potent indirect action. The a-adrenergic receptor stimulation (direct-acting or indirect-acting) by these drugs gives rise to decongestion of the mucous membranes of the nose. The drugs with mixed action administered topically act directly, but if they are administered orally, they reach lower concentrations in the biophase, resulting in mainly indirect action.

• short-actingdrugs (4 to 6 hours), e.g. ephedrine, phenylephrine, propylhexedrine, naphazoline and tetrahydrozoline;
• intermediary actingdrugs (8 to 10 hours), e.g. xylometazoline;
• long-actingdrugs (12 hours), e.g. oxymetazoline.

Typically administered topically (nasal spray)

What is rhinitis medicamentosa?  How is it treated?

Also known as 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 a‑adrenergic receptors on the blood vessels, rendering them unresponsive towards the a‑agonists. Receive local corticoid 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?

The first-generation antihistamines are multipotent competing antagonists and also block muscarinic receptors. Antimuscarinic drugs reduce the secretions of both the upper and lower airways and are, therefore, frequently included in preparations for colds to clear up rhinorrhoea.  They can, however, cause sedation and therefore negatively influence the ability to concentrate. The second-generation antihistamines do not block muscarinic receptors and are useful in the long-term or short-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. They also do not cross the blood/brain barrier and thus rarely cause sedation

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

Corticosteroids: Used in allergic rhinitis, nasal polyps, inflammatory rhinitis and reversal of rhinitis, nasal spray

Anti-allergic drugs: Nasal vestibule staphylococci infection, prophylactic treatment of allergic rhinitis, nasal spray

Salt solution: dilutes mucus during sinusitis, nasal rinse/lavage 

• 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.

Which vascular changes can be observed before and during migraines?

Once chemicals in the brain are released they move to the meninges of the brain which leads to inflammation and swelling of the blood vessels. This causes an increase in blood flow around the brain. This is what is suspected to cause the throbbing pain that people experience during a migraine.

What is the role of serotonin in migraine headaches?

Serotonin is needed for communication between nerve cells. It can lead to the narrowing of blood vessels in the body, which will counteract the throbbing pain that is felt. If serotonin levels - or oestrogen levels in women - change, the result can be a migraine.

How is ergotamine used during a migraine attack?

Take at the first sign of a migraine. Place a tablet under your tongue and allow it to dissolve. Take 1 tablet every 30min as needed. no more than 3 tablets within 24hours.

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

Side effects: Nausea, vomiting, diarrhoea, hallucinations, gangrene (due to ergotamine being a strong vasoconstrictor), tachycardia, rebound headache

Contraindications: Cardiovascular disease, hypertension, liver and kidney impairment, pregnancy, psychosis

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

• Analgesics (Aspirin/paracetamol?NSAIDs) - relieves pain
• Antiemetics (Metoclopramide, Cyclizine) - Relieves nausea and vomiting
• Ergotamine - vasodilator, decreases pain
• 5-HT1D agonist (Sumatriptan / Zolmitriptan) - constricts large arteries, inhibits trigeminal nerve transmission & vasoactive peptide release.
• Sedative (Diazepam) - sedates the person so that they can sleep.

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

• β-blockers (Propranolol)

Side effects: fatigue

Precautions:

• α2 agonist (Clonidine)
• Ca²⁺ blockers (Verapamil)
• TCA (Amitriptyline)

Side effects: dry mouth

• Anti-epileptic drugs/anti-convulsant (Valproic acid, valproate, topiramate)

Side effects: nausea

• 5-HT2 antagonist (Pizotifen, Cyproheptadine, Methylsergide)

Precautions: There is strong evidence to support the use of metoprolol, timolol, propranolol, divalproex sodium, sodium valproate and topiramate for the prevention of migraines

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

Selective inhibitor of microtubule and spindle formation in macrophages and leukocytes. Also inhibits chemotaxis. ↓Leukocyte metabolism & lactic acid production & ↑pH

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 and inflammation.

Side Effects: GIT, gastric bleeding, liver & kidney damage, bone marrow suppression, peripheral neuritis, alopecia

Dose: 0.5-1 mg

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

Acute Gout:

NSAID's: Indomethacin, Diclofenac, Piroxicam, Naproxen

Spindle poison: Colchicine

Glucocorticoids: Betamethasone, Prednisone

Chronic Gout:

Uric acid synthesis inhibitors: Allopurinol

Uricosuric drugs: Probenecid, Sulfinpyrazone

Urine alkalizers: Citro-soda

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

Uricosuric drugs. They Compete with uric acid for reabsorption in proximal tubule in kidney. At low concentration these drugs compete with uric acid for secretion out of tubule and increase initial [uric acid].

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

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.

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

Peripherally: Paracetamol is a weak COX1 & COX2 inhibitor. It has analgesic & antipyretic effects and weak to no anti-inflammatory action. There is also no effect on platelet aggregation, which is the opposite in Aspirin. Aspirin decreases platelet aggregation and inhibits COX1&2 irreversibly.

CNS: COX 3 inhibition, modulate body's endogenous cannabinoid (cannabis) system & 5-HT descending pain pathways AND inhibits NMDA receptors, reducing nociception (blocks the receptors thus neurotransmitters cannot bind thus perception of pain is blocked).

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

It is used in the treatment of light to moderate pain of somatic origin, when an anti-inflammatory effect not needed.  Acute pain, chronic pain and fevers. Paracetamol is used when anti-inflammatory effects are not needed and it is used in patients where NSAIDs are contraindicated.

Name side-effects that can occur with paracetamol use.  Concentrate only on general side effects and not on acute paracetamol overdose

skin rash and urticuria

Due to the ready availability of paracetamol and the general perception by the public that paracetamol is a very safe drug, paracetamol poisoning (by accident/intentional) is fairly common.  Compile a report in which you discuss acute paracetamol toxicity, stressing the dose, signs and symptoms and treatment.  In your textbook, as well as in the SAMF, there is valuable information that you can use

Signs and symptoms:

Nausea, vomiting, abdominal pain, fatigue and weakness in the beginning.

Renal impairment & hepatotoxicity occurs 24-48h after overdose with light subcostal pain, tar liver, jaundice, renal insufficiency, liver necrosis and death.

Dose:

10-15g can be fatal.

Chronic use of 2g / day can also lead to paracetamol poisoning.

Treatment:

• Within 1h of overdose: Induce vomiting, gastric lavage, activated charcoal.
• Liver damage can be prevented with large dosage of NAC if given before 12hrs after ingestion. Given iv (150mg/kg) / orally (140 mg/kg). NAC less useful after 12hrs.
• Immediate supplementation of –SH groups to supplement glutathione in liver and prevent liver cell necrosis.
• N-acetylcysteine ​​(Parvolex®) administered within 8-12 hours IV.
• Initial dose : 150mg/kg in 200ml 5% glucose over 15 minutes, thereafter 50 mg/kg in 500 ml 5% glucose over 4 hours, thereafter 100 mg/kg in 1 000 ml 5% glucose over 16 hours.
• Oral Treatment: acetylcysteine ​​(Solmucol®, ACC®), 140mg / kg or carboscistein (Mucosirop®, Flemex®) 150mg / kg
• NB: treatment only effective within 10hrs of poisoning

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 SSRI that is approved by the FDA in the treatment of OCD, depression and other conditions. However, it is not approved by the FDA for the treatment of infections (NIH, 2021).

Fluvoxamine has a high affinity for the S1R which is the ER-resident protein sigma-1-receptor. This receptor is responsible for restricting endonuclease activity of the ER stress sensor, IRE1 and it restricts the expression of cytokines as well. This does not mean that fluvoxamine inhibits the inflammatory signaling pathways, it only inhibits the synthesis of the inflammatory cytokines. Cytokine expression is what leads to inflammation in COVID-19, and fluvoxamine decreases the inflammatory response in leukocytes (CIDRAP, 2021).

Due to this, fluvoxamine is currently undergoing studies to determine its effectiveness in the treatment of COVID-19

References:

NIH (National institute of health). 2021. https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/ Date of access: 13 Oct. 2021

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-treatment Date of access: 16 Oct. 2021.

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

This vasodilation is dependent on the endothelium and factors inside the endothelium. The intracellular calcium levels are raised by endothelium-dependent vasodilators such as acetylcholine. NO is formed as a result of this, which is an endothelial-derived relaxing factor. Now NO moves to the vascular smooth muscles to cause its vasodilating effect

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 continuously synthesized whether suitable substrate is available or not.

Induced enzymes are enzymes that can only be detected after a certain substance (inducer) has been added.

Because Constitutive enzymes are constantly produced, they have a greater chance to be influenced by pathology than the temporary induced enzyme.

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

Septic shock results when infectious organisms that are found in the bloodstream induce a profound inflammatory response and then causes haemodynamic decompensation. The components that are found in the bacteria, such as cytokines, can lead to the formation of iNOS in macrophages, smooth muscles, etc. If the NO is widespread it then results in severe hypotension, shock and death.

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?

NOS enzyme inhibitors are released by the body, this binds competitively to the arginine binding site in NOS, thus arginine cannot be converted to NO.

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

NO that is released can, due to its role in Prostaglandin synthesis, have an iflammatory response when there is an injury or infection. This causes erythema (redness of the skin), vascular permeability and oedema (acute inflammation).

advantage: NO and peroxynitrates that are formed during inflammation are important microbicides.

disadvantage: an overproduction of NO can lead to tissue damage, psoriasis lesions, etc. It can also influence disease pathology.

In which possible neurological and psychiatric diseases is NO involved? 

Parkinson's disease, stroke and amyotrophic lateral sclerosis.

Why do you think aspirin is contraindicated in people with allergic asthma?

It blocks both COX 1 and 2, therefore, there is more arachidonic acid is available for the production of leukotrienes, hence more leukotrienes are produced, this leads to bronchoconstriction, which is not good for asthma patients.

Arachidonic acid is the most important precursor of the eicosanoids, but how is this fatty acid released from the cell membrane, and by which stimuli?

• Arachidonic acid (AA) must first be released from membrane phospholipids for eicosanoid synthesis to occur.
• There are at least 3 classes of phospholipases contributing to AA release form membrane phospholipids namely:
  • Cytosolic PLA₂ (phospholipase A₂)
  • Secretory PLA₂ (calcium dependent)
  • Calcium independent PLA₂ (chemical and physical stimuli activate Ca²⁺ translocation of PLA₂ to the plasma membrane where it releases arachidonic acid for synthesis of eicosanoids.)

Apart from prostanoids and leukotrienes, which other non-eicosanoid product of cell membrane hydrolysis is strongly involved in asthma?

Why would you say a COX II-inhibitor, and not a COX I-inhibitor, has a selective action in inflammatory reactions?

COX 1: always present in the body, has housekeeping functions such as gastric epithelial cytoprotection.

COX 2: is readily inducible, its levels being dependent on the stimuli. It is common in the kidney, vascular tissue. It’s release is due to stimulus of inflammation, shear-stress, growth factors. Tumour promoters etc.

a drug that inhibits each of the following enzymes: phospholipase A; cyclooxygenase; lipoxygenase,

phospholipase A: hydrocortisone

cyclooxygenase: Aspirin

lipooxygenase: zileuton

a drug that can act antagonistically or agonistically at prostaglandin and leukotriene receptors

Misoprostol

Aspirin inhibits platelet aggregation because it inhibits thromboxane synthesis and not prostacyclin synthesis.  How does it happen?

Irreversibly block cox1 & cox2

How is alprostadil advantageous in the treatment of congenital heart defects?

This is given as infusion to patient to keep heart valve open during surgery.

How is misoprostil of value in the treatment and prevention of gastric ulcers?

This protects the stomach lining, by increasing mucous production and decreasing acid secretion.

Prostaglandin is possible of value in asthma.  Which PG_E2- or PGF_2A-analogues will be effective in such a case?

Epoprostenol

How is latanoprost of value in the treatment of glaucoma?

Increased outflow of aqueous humor.

Which vascular changes can be observed before and during migraines?

Once chemicals are released, they move to the outer layer of your brain - the meninges - resulting to inflammation and swelling of blood vessels, leading to an increase in blood flow around the brain. This is probably the result of the throbbing, throbbing pain that most people experience during migraines.

What is the role of serotonin in migraine headaches?

Serotonin is a chemical that is needed for communication between nerve cells. It can lead to narrowing of blood vessels throughout the body. If serotonin or oestrogen levels change, the result is for some migraines. Serotonin levels can affect both sexes, while fluctuating oestrogen levels affect only women.

How is ergotamine used during a migraine attack?

Take ergotamine as soon as migraine symptoms starts. Place a tablet under your tongue and let it dissolve. Take 1 tablet every 30 minutes as needed. Do not use more than 3 tablets within 24 hour period.

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

The side effects are: Overdose can cause vomiting, confusion, drowsiness, weak wrists in your legs and arms, numbness and tingling or pain in your hands or feet, blue fingers or toes, fainting and seizures (convulsions).

The contraindications: high blood pressure, coronary heart disease, cerebral ischemia, lack of blood supply to the brain, Raynaud's phenomenon, a condition in which blood vessels contract too much with cold or tension, peripheral vascular disease, thrombophlebitis, an inflamed vein due to a blood clot

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

Currently, non-steroidal anti-inflammatory drugs (NSAIDs) and triptans (serotonin 5HT1B / 1D receptor agonists) are recommended for the acute treatment of migraine attacks. Metoclopramide or domperidone are useful for taking NSAIDs and triptans. In very severe attacks subcutaneous sumatriptan is the first choice

Migraine is a common neurological disorder with a serious socioeconomic burden. By blocking cyclo-oxygenase, non-steroidal anti-inflammatory drugs (NSAIDs) reduce the synthesis of prostaglandins, which are involved in the pathophysiology of migraine

Triptans are selective 5-HT1 receptor agonists, indicated in severe migraine attacks. These drugs work mainly by vasoconstriction in the cranial blood vessels. However, vasoconstrictive effects outside the central nervous system are also possible

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

First-line therapies for the prevention of migraine in adults include propranolol (Inderal), timolol (Blocadren), amitriptyline, divalproex (Depakote), sodium valproate and topiramate (Topamax)

The side effects

propanolol - fatigue

timolol - fatigue

amitriptyline - dry mouth

divalproex (Depakote) - sedation

topiramate (Topamax) - nausea

The precautions

There is strong evidence to support the use of metoprolol, timolol, propranolol, divalproex sodium, sodium valproate and topiramate for the prevention of migraines.