Blog#2.4

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

Vasodilation caused by substances that induce vasodilation and comes from the endothelium Different stimuli that are found in endothelial cells causes Nitric Oxide synthesis which in turn 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.  

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 Nitric Oxide  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  due to its role in prostaglandin synthesis in the COX2 pathway, 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. 

In which possible neurological and psychiatric diseases is NO involved? 

Parkinson’s disease, stroke.

Blog #2.5

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 sppecific receptor is responsible for the restriction of endonuclease activity of the Endoplasmic reticulum stress sensor, IRE1. It restricts cytokine expression. Fluvoxamine does not inhibit inflammatory signaling pathways. The cytokine expression acts as an inflammation-causing symptom in COVID-19. With this, Fluvoxamine decreases the inflammatory response in human blood leukocytes. therefore, fluvoxamine is being researched as a possible treatment option for the Covid-19 virus.

Study unit 3.1

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

Beta-adrenoceptor agonists stimulate adenylyl cyclase (via the β2-adrenoceptor–Gs-coupling protein-adenylyl cyclase pathway) and increase cyclic adenosine monophosphate (cAMP) in smooth muscle cells . The increase in cAMP results in a powerful bronchodilator response.

• 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?

Primary mechanisms: Bronchodilation and smooth muscle relaxation

Mechanism Of Action of B-2 agonists: stimulate adenyl cyclase which causes cAMP to increase in bronchial smooth muscle which thereafter causes bronchodilation

Molecular pharmacology: Bronchodilation and Vasodilation of smooth muscle (SM) vessels are effects of B2 agonist stimulation. At high doses also B1 stimulating effects which cause possible side effects such as tachycardia.

• 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.

• Stimulant, increased alertness, insomnia, high doses:  CENTRAL NERVOUS SYSTEM

• Elevated ino- and chronotropy: CVS

• Increased gastric acid and digestive enzyme secretion: GASTRO INTESTINAL TRACT

• Increased glomerular filtration rate, diuresis (Renal): KIDNEYS

• Strengthens contraction of diaphragm: SKELETAL MUSCLE

• 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?

Theophylline has a very narrow therapeutic window, patients are at an increased risk of serious theophylline toxicity. Since nearly all of theophylline dose is biotransformed, drugs influencing microsomal enzyme systems in the liver may affect the elimination of theophylline. Other integrated mechanisms (e.g. hepatic uptake) may also be altered by concurrent administration of other drugs. Whatever the mechanism, the interaction may be sufficient to necessitate adjustment of the theophylline dosage, preferably guided by plasma theophylline determinations. Many drugs have been found to increase or decrease the clearance of theophylline, by interaction with one or more of the variants of the cytochrome P450 drug-metabolising system. Theophylline is susceptible to alteration of its clearance because of the particular forms of the P450 system involved, because its metabolism is saturable, and/or because 90% of its elimination is via metabolism. Drug examples include:

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

By aerosol, these drugs competitively block muscarinic receptors in the airways and effectively prevent bronchoconstriction mediated by vagal discharge. If given systemically (not an approved use), these drugs are indistinguishable from other short-acting muscarinic blockers.  Because these agents are delivered directly to the airway and are minimally absorbed, systemic effects are small. When given in excessive dosage, minor atropine-like toxic effects may occur.

• 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’s clearance has been found to be decreased by around 25%, but often by far more, by erythromycin and ciprofloxacin.

Blog #3.5
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 fluidity, as well as daily mucus removal and antibiotics if an infection is present.

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.
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.

Blog #3.4
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, causing vasoconstriction of the mucosal blood vessels (decrease in oedema of the nasal mucosa) . 
They can be short acting (4 hours), intermediate acting: (8-10 hours) and long acting (12 hours)

They are typically administered :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 due overuse of nasal decongestants. This  can cause prolonged vasoconstriction of the nasal blood vessels 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 so they are usually used in cold preparations in rhinohorrea. They are sedative and can thus decrease concentration.

Second gen  only antagonise H1 receptors hence 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.

Name of Blog: Blog #3.2 Danielle Kleynhans (34943366)

Answer the following:
Give your own definition of COPD.
• A chronic bronchiole inflammatory disease that’s origin is hereditary or due to emphysema and which symptoms cannot be cured but rather controlled. It is identified by permanent change in bronchial physiology and impaired airflow.

Briefly describe the proposed aetiology and pathophysiology of chronic bronchitis and emphysema.
Chronic bronchitis 
Non-specific obstructive airway disease, characterized by:
• increase in Mucus secretion
• decreased mucosal clearance
• Repeatedly occurring bacterial respiratory infections
• Physical changes in bronchial wall structure 
• Chronic cough due to sticky mucus

Emphysema: 
develops due to smoking and irritants
• Irreversible dilation of respiratory bronchioles and alveoli due to structural damages that have occurred over time.
• Air is trapped in lungs - difficult exhalation

Which types of therapy are included in the treatment of a COPD patient?
Anticholinergic drugs: Ipratropium
Corticosteroids: Beclometasone
Methylxanthine: Theophylline 
Long acting B2 agonist: Salmetorol
Other drugs: Raflumikast

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

Bronchial asthma is a inflammatory disease and would there require an corticosteroid or methylxanthine drug which has an anti- inflammatory process.

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

It improves diaphragmatic contractility of the respiratory muscles which could aid in the breathing of COPD patients 

What is the role of oxygen therapy 
 if you have low levels of oxygen in your blood (hypoxia), it is used to prevent right-sided heart failure.  Oxygen may be given in a hospital if you have sudden increased shortness of breath (COPD exacerbation) for immediate relief.