Question 1: Briefly explain what cystic fibrosis is and how dornase alpha acts to solve the problem

It is a genetic defect that can cause a decrease in secretions in many organs. The most problematic symptom is in the airways. The airway has a very thick sticky mucus secretion which allow a good environment for bacterial infections. The continuous infections that are present cause continuous chemotaxis of neutrophils which later cause deposits of DNA, as a result the mucus becomes even more sticky. it is very difficult to clear the mucus therefore more infections occur. 

Dornase alfa hydrolyses extracellular DNA from neutrophils in the bronchial mucus, this causes an increase in the liquidity. 

Question 2: Briefly explain what neonatal respiratory distress syndrome is, what the general treatment strategies involve and hw cortisone and exogenous surfactants solve the problem

The surface active material that covers the respiratory tract of the airway is only formed during the final weeks of pregnancy. When premature babies are born the surface active material is not formed, this causes gas exchange to be disrupted and the lungs might collapse. Treatment needs to be followed quickly in order to save the babys life. 

The general treatment options would be: oxygen as this ensure oxygenation, ventilation for positive pressure and medications (exogenous surfactants like poractant alfa and beractant )

Cortisone increases surfactant production and can be administered prophylactically 

Exogenous surfactants increase the lungs surfactant 

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

Oxygen is given in order to guarantee oxygenation. A continuous oxygen pressure from the ventilator helps increase respiration and allows the alveoli to stay open and not collapse. The arterial partial oxygen however needs to be continuously monitored.  In order for respiration to take place there needs to be enough oxygen present. It is therefore administered to prevent hypoxia. However, when oxygen is inhaled in large quantities or over a long time it has toxic effects. It can cause inter alia, reduced gaseous exchange, hypoxia and in very severe cases even death. In neonates it can also cause retinal damage which leads to blindness

Question 4: Briefly explain what neonatal apnea is and how the methylxanthines solve the problem. which methylxanthine is used ?

It occurs when your respiratory center in the medulla of a premature baby has not been able to develop enough to stimulate continuous breathing. Therefore, making the breathing center very sensitive to stimulation and effect of CO2. Apneas typical duration is not longer than 15seconds and comes together with bradycardia. The continuous episodes of apnea can lead to neural damage. 

Methyxanthines like caffeine and theophylline stimulate the CNS. IV administrations tend to aid the problem. Therapy will be stopped usually after a few weeks in the ICU. The neonate will thereafter receive oxygen therapy. It is important to always monitor the oxygen levels in the blood.

Question 1: What are the general causes of rhinitis and rhinorrhea?

Rhinitis is linked to cold and flu.

Mucosal rhinitis which is linked to sinusitis.

Allergic rhinitis is linked to allergen exposure and IgE mediated inflammation.

Non-allergic rhinitis is he physiological reaction because of stimuli like the cold or smoke.

Question 2: Which drugs can be used for the treatment of rhinorrhea? name examples of each group

• Alpha1-agonist (naphazoline)
• Corticosteroids ( Budesonide)
• Mast cell stabilizer (ketotifien)
• Antihistamines (loratidine)
• Mucolytics (Mesna)
• Diverse drugs (normal saline)
• Antibiotics (neomycin)

Question 3: How do decongestants differ with respect to the moa and duration of action? how are they administered typically?

MOA: decongestants present are alpha adrenoceptor sympathomimetics, They therefore cause vasoconstriction, as a result reducing nasal airway resistance and allows breathing through the nose.

Duration of action: they provide quick relief that can last up to 12 hours however, they can only be used for 5-7 days.

Decongestants are administered topically by metered-dose sprays, which is the safest.

Question 4: What is rhinitis medicamentosa ? How is it treated?

Rhinitis medicamentosa is a condition that develops if the topical decongestants are repeatedly used for more than 7 days. this happens when an overstimulation of the alpha receptor (in the nasal mucosa) occurs. Therefore leading to the drying of the mucosal tissue. As a result you are left with a blocked nose that can be treated with cortisone nasal sprays.

Question 5: How does the first and second gen of antihistamines differ with respect to the mechanisms according to which rhinitis and rhinorrhea are delivered? What are the advantages of the second gen of antihistamines? why should they not be used to relieve cold rhinitis?

1st gen antihistamines are used for non allergic rhinorrhea since they reduce inflammation in the nose. They also treat the symptoms.

2nd gen antihistamines are used to treat allergic rhinitis since they inhibit the release of histamine from  mast cells as well as other inflammation mediators. The advantages would be that they have almost no CNS distribution and have a low incidence to patients who have sedation and anticholinergic side effects.

However, antihistamines should never be used to alleviate cold rhinitis since symptoms which are caused by the bodys response are not related to histamine production. Antihistamines will have no effect. Therefore, we can say that histamine is not the major cause of a runny nose.

Question 6: When are corticosteroids, anti-allergic drugs, mesna and normal salt solution valid and how are they administered?

• Corticosteroids: they are acceptable for the use of allergic rhinitis and is administered topically via nasal spray.
• Anti-allergic drugs: they are acceptable for prophylactic treatment of allergic rhinitis, administered topically via nasal spray.
• Mesna: this is acceptable for sticky nasal secretion, since it aids the mucus to become more of a liquid, administered topically via nasal spray.
• Normal salt solution: acceptable for humidifying dry and swollen mucus membranes of your nose during dry, cold weather, allergy like hay fever, nose bleed and other irritants, it is administered topically via nasal drops.

Question 1: Giver your own definition of COPD

It is a combination of lung diseases that prevent airflow resulting in difficulty in breathing. Some of the most common conditions that make up COPD are: Emphysema (condition where the walls of the air sacs of the lungs are damaged), bronchial asthma (condition where a persons airway become swollen and produces extra mucus which makes breathing difficult) and chronic bronchitis (inflammation of lining of bronchial tubules). Damage to the lungs from COPD can not be reversed.

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

• Emphysema:                                                                                                                                                   

The cause of emphysema is generally continuous exposure to irritants that  damage your lungs and their airways.  The damage done to the alveoli eventually leads to reduced elasticity and over-inflation. This therefore causes swelling of the bullae where the CO2 becomes trapped. Due to this reason the lungs are being deprived of continuous flow of oxygen therefore causing deeper breathing. Emphysema is therefore known as a lung condition that causes shortness of breath.

• Chronic bronchitis:

It is a non-specific obstructive airway disease which is characterized by: reduced mucus secretion and mucosal clearance, recurring bacterial respiratory infections, changes in bronchial walls and chronic cough due to sticky mucus. The bronchial lining becomes inflamed and continuous exposure to smoke, excessive dust or chemicals will eventually cause damage to the bronchioles. Chronic bronchitis is due to hypersecretion of mucus by the goblet cells. The epithelial cells lining the airway responds to infectious stimuli by freeing inflammatory mediators.

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

• stop smoking.
• Airway obstruction: Bronchodilators.
• Hypoxia: Oxygen inhalation.
• Poor lung capacity: Regular exercise.
• Bacterial infection: antibiotics against influenza.
• surgery: lung transplant.

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

Ipratropium is a muscarinic Ach receptor antagonist which prevents the function of parasympathetic nervous system. The function includes: the production of bronchial secretions as well as constriction. If this is prevented it will result in bronchodilation and less secretions. Ipratropium is therefore more effective in the treatment of chronic bronchitis since it is characterized by increased mucus secretion. With bronchial asthma, the increased mucus secretion does not have the same effect.

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

Theophylline improves ventilation response, decreases hypoxia and dyspnea in COPD patients. It causes the smooth muscle relaxation which further causes bronchodilation. This allows for easier flow of air to the bronchial air passage therefore, significantly improves breathing.

Question 6: What is the role of oxygen therapy in COPD?

Increases the amount of oxygen that flows into your lungs and bloodstream and as a result this improves breathing.

Question 1: Give a short critical explanation of the rationale of using fluvoxamine (a selective serotonin reuptake inhibitor (SSRI)) in the treatment of Covid19 patients.

Fluvoxamine is an SSRI which has been FDA approved in the treatment of depression, OCD etc, but has not been approved for the treatment of infections (NIH, 2021). 

Fluvoxamine has a great affinity for S1R. This receptor controls the endonuclease activity of the ER stress sensor, IRE1 as well as controlling expressions of cytokines. This therefore means that Fluvoxamine hinders the inflammatory signaling pathways but hinders inflammatory cytokines synthesis. Upon further research, cytokine expression causes inflammation in Covid19. 

As a result Fluvoxamine still needs further research to determine its success in the treating Covid19 patients. 

References: 

NIH (National institute of health). 2021. https://www.covid19treatmentguidlines.nih.gov/therapies/immunomodulators/fluvoxamine/ Date of access: 19 Oct. 2021

NIH (National institute of health). 2021. https://pubmed.ncbi.nlm.nih.gov/33403480/ Date of access: 19 Oct. 2021

Question 1: What do you understand by the term "endothelium-dependent" vasodilation? Explain

Endothelium-dependent vasodilators like bradykinin increase the intracellular calcium levels in the endothelium. This therefore leads to the synthesis of NO (an EDRF) in the endothelium. NO them makes its way to the vascular smooth muscle to cause a vaso-relaxing effect.

Question 2: When we talk about NOs enzyme, what is meant by "constitutive" and "inducible" enzymes and what are the pathological and physiological implications thereof?

They are enzymes that are repeatedly being synthesized irrespective of physiological need. They have a greater physiological and pathological importance because they are always present in one are. 

On the other hand, Induced enzymes are enzymes which emerge after a particular substance has been added. This implies that the enzyme is in fact present before a substance, therefore the body has to excrete a substance before the enzyme "works". The effects are small.

Question 3: Explain how NO contributes to fatal pathology of septic shock

It is a systemic inflammatory response which is caused by an infection. Some components which are present in bacteria (endotoxins, cytokines and tumor necrosis) cause the formation of iNOS in macrophages, smooth muscle cells etc. formation of NO in a large area therefore leads to severe hypertension, shock and may also lead to death. 

Question 4: Which autacoids mechanism of action depends on effects on the guanylyl cyclase-cGMP system

Nitric oxide (NO)

Question 5: NO may be toxic to the cell. Which mechanisms are available to the body to counter this detrimental effect of NO?

our bodies release NOS enzyme inhibitors that competitively bind to the binding site of arginine  in NOS. Thus, arginine is not converted to nitric oxide. 

Question 6: Name a way in which NO can act pro-inflammatory. Give examples of where it will have advantages or disadvantages. 

When you body reacts to infection or even injury it leads to the activation of leukocytes and release of inflammatory mediators. This causes an increase in iNOS levels in leukocytes. The NO produced is an important microbial agent. the function of TH1 which synthesizes NO. This is a good protective response. The vasodilator effects of NO and effects of COX2 carry a huge role in inflammation, it causes red skin, it increases vascular permeability and increases edema in acute conditions. The disadvantage of NO however would be, in both acute and chronic inflammation the excess NO production may cause tissue damage, psoriasis lesions, airway epithelium in asthma patients and inflammatory bowel lesions.

Question 7: In which possible neurological and psychiatric disease is NO involved?

Parkinson's disease, stroke and amyotrophic lateral sclerosis, which result because of over stimulation of NMDA receptors and therefore causing an increase in the synthesis of NO which inevitably causes excitotoxic neuronal death. 

Question 1: In which diseases are angiotensinogen levels increased? What are the implications of this?

They are increased by estrogens, corticosteroids, thyroid hormones and ANG II. However, these levels are increased when women take estrogen from oral contraceptives and during pregnancy. Therefore explaining the raised angiotensinogen concentration which may result in hypertension. 

Question 2: Why do drugs which inhibit the angiotensin system by acting on angiotensin receptors have fewer side effects than those that inhibit ACE?

Since there is an increase in the levels of bradykinin, ACE inhibitors can lead to angioedema and a dry cough.

Question 3: In which way does ACE inhibitors have a two-folded mechanism of action in the treatment of hypertension?

ACE inhibitors block the conversion of ANG I to ANG II. They also prevent the breakdown of substances namely, enkephalins, bradykinin and substance P. The Action of ACE inhibitors which hinders substances like bradykinin and contributes to lowering blood pressure. 

Question 4: At which type of angiotensin receptor does Losartan and similar drugs act? Do they have any effect, direct or indirect, at other angiotensin II receptors?

Drugs act on  AT1 receptors and when ANG II is increased they act on AT2 receptors. 

Question 5: What are the physiological effects of kinins on arteries and veins? Do other autacoids play a role? Explain

They cause vasodilation in the arteries, this is because of the direct inhibitory effect of kinins on the arteriolar smooth muscle. It can also be explained by the release of vasodilator prostaglandins (PGE2 and PGI2) or NO. Kinins cause the vein to contract because of the release of vasoconstriction prostaglandins (PGF2 alpha) or the direct stimulation of the venous smooth muscle. Autacoids like bradykinin is a potent vasodilator. 

Question 6: Which receptor is probably  the most involved in the important clinical effects of kinins?

B2 receptor.

Question 7: In which way are natriuretic peptides possibly effective in the treatment of hypertension, as well as congestive heart failure?

Natriuretic peptides (namely, ularitide, carperitide, nesiritide and urodilatin) causes natriuresis and vasodilation in the treatment of congestive heart failure. 

Question 8: what is neprylisin and what is the rationale for inhibiting its action in the treatment of heart failure? can you name the drug being used for such? 

It is a key enzyme in the breakdown of natriuretic peptides. The initial motive of neprylisin in cardiovascular disease was to increase endogenous natriuretic peptide levels, therefore achieving vasodilation and natriuresis.

Question 9: Give examples of endothelium-derived vasodilators and vasoconstrictors.

• Vasodilator: PGI2 and Nitric oxide.
• Vasoconstrictors: ET1 and the receptor subtypes ETA and ETB.

Migraine Pathology:

Migraines that are involved in the release of peptide neurotransmitters, a peptide that is associated with CGRP (from the nerve through the cerebral arteries). Therefore, this neurotransmitter induces vasodilation and extravasation of blood plasma and plasma protein into the perivascular oedema, as a result causing mechanical stretching in the dura and the pain nerve endings are activated. 

Migraine treatment:

• Anticonvulsants have prophylactic efficacy for migraines since they suppress excessive activation of the trigeminal nerve endings.
• Anti-inflammatory pain relievers have high efficacy as well.  
• Calcium blockers  and beta blockers are also effective for treating migraine prophylaxis in many patients. 
• Triptans are considered therapy for migraine and the partial agonists of serotonin 1B/1D receptors. It increases intercranial vasoconstriction which prevents vasodilation, which causes pain by stretching the sensory nerve endings. These agents also play a role in decreasing  the release from CGRP and as a result will reduce perivascular oedema in the intercranial circulation. 
• Lastly, ergot alkaloids have a mixed partial agonist effect on alpha-adrenoceptors and serotonin-2-receptors. They therefore block the alpha-agonist vasoconstriction and cause a noticeable contraction of smooth muscle (thus preventing vasodilation which leads to the pain)

Verduidelik kortliks wat sistiese fibrose is en hoe dornase-alfa werk om die probleem op te los?

• Sistiesefibrose is genetiese metaboliese siekte(verlaag DNase 1) wat lei tot verlaagde sekresies in verskeie organe. Die manifestasie in die lugweë is die mees prominente en problematiese simptoom, die mucus sekresies in die lugwe is besonder dik en taai wat die ideale omgewing vir bakteriële infeksies skep.
• Dornase-alfa (rhDNase) inhalasies help om die probleem op te los deur proteïene (ekstrasellulêre DNS vanaf die neutrofiele) in die brongiale mucus te hidroliseer om vloeibaarheid te verbeter.

Verduidelik kortliks wat neonatale respiratoriese noodsindroom is, wat die algemene behandelingstrategieë behels en hoe kortisoon en eksogene surfaktante werk om die probleem op te los?

• Dit is bekend as hialienmembraansiekte wat by premature babas voorkom waar die oppervlak-aktiewe stof wat die lugweë bedek en noodsaaklik is vir gaswisseling ,eers kort voor geboorte gevorm word en dit kan veroorsaak dat die longe dus kan platval.
• Behandeling strategieë sluit in:

• Suurstofom oksigineringteverseker
• Ventilator gebruikvirpositiewedruk
• Verhoogdesuurstofoorlang termynlei tot retinaleskadeenblindheid
• Gm: eksogene surfaktant: beraktant, poraktant alfa. Word aan die neonaat toegedien om longsurfaktant aan te vul.
• Kortikosteroïede soos betametasoon–word profilakties aan moeder voor kraam toegedien om baba se surfactant produksie te inisieer.

Wat is die rol van suurstofterapie by neonatale respiratoriese noodsindroom?  Wat behels die gevare van suurstoftoksisiteit?

• Suurstof terapie word toegedien om oksigenering te verseker.
• Langtermyn se verhoogde suurstof kan lei tot retinale skade asook blindheid, verminderde gaswisseling, hipoksie en in uiterste gevalle, die dood

Verduidelik kortliks wat neonatale apnee is en hoe die metielxantiene werk om die probleem op te los.  Watter metielxantiene word gebruik?

• Asemhalingsentrum in brein nog nie volledig ontwikkel om voordurende asemhaling te stimuleer nie. Dit kom by pasgebore en premature babas voor. Die asemhalingsentrum is dus nog onsensitief vir die stimulerende effek van koolsuurgas.
• Metielxantiene help om die probleem op te los deurdat dit die SSS stimuleer. Soms word daar suurstof terapie aangedui en voortdurende monitoring van die suurstofvlakke in die bloed.
• Metielxantiene is bv. Kaffeïen, teofillien IV vir paar weke

Wat is die algemene oorsake van rinitis en rinoree?

• Algemene oorsake is allergie, verkoue, chemieseof gm skade, kouelug of fisiese skade.

Watter geneesmiddelgroepe kan by die behandeling van rinoree gebruik word?  Noem voorbeelde by elke groep.

• Alfa 1 agoniste (dekongestante) - Efedrien, fenielefrien
• Antihistamiene – Difenhidramien, prometasien
• Kortikosteroïde – Betametasoon, prednisoon
• Mastselstabiliseerders – Natriumchromoglikaat, nedochromielnatrium
• Mukolitika – Mesna, asetielsistein
• Antibiotika - Mupirosien, neomisien, topikaalbinneneusholte
• Diverse – Stoom, soutoplossing, mentol

Hoe verskil die dekongestante onderling ten opsigte van werkingsmeganisme en werkingsduur?  Hoe word hulle tipies toegedien?

• MVW: Simpatomimetiese agente is, alfa 1 agoniste wat vasokonstriksie van die mukosale bloedvate veroorsaak, verlaag dus edeem van die nasale mukosa.

Die a-agoniste gee kan ook verdeel word in:

• kortwerkende middels (4 tot 6 ure), bv. efedrien, fenielefrien, propielheksidrien, nafasolien en tetrahidrosolien
• intermediêrwerkende middels (8 tot 10 ure), bv. silometasolien
• langwerkende middels (12 ure), bv. Oksimetasolien.
• Hulle word dus topikaal of oral toegedien – soos ʼn sproei

Wat is rhinitis medicamentosa?  Hoe word dit behandel?

• Rhinitis medicamentosa (privinisme) en terugslagrinitis kan met oordosering van dekongestante ontstaan.  Privinisme is ’n toestand wat ontstaan na chroniese behandeling met dekongestante. Daar is gedurig vasokonstriksie met swak lokale bloedvoorsiening wat kan aanleiding gee tot skade van die neusslymvliese met permanente inflammasie en swelling. Persone met privinisme behoort behandeling te staak en tydelik lokale kortikoïedterapie te ontvang.

Hoe verskil die eerste en tweede generasie antihistamiene ten opsigte van die werkings­meganismes waarvolgens rinitis en rinoree verlig word?  Wat is die voordele van die tweede generasie antihistamiene?  Waarom behoort hulle nie gebruik te word om verkouerinitis te verlig nie?

• Die eerste generasie antihistaminika MVW: Multipotente kompeterende antagoniste en blokkeer ook muskariniese reseptore.  Antimuskariniese middels verminder die sekresies van die hoër en die laer lugweë, en kan dus by verkouepreparate ingesluit word om rinoree op te klaar.
• Die tweede generasie antihistamiene MVW: Blokkeer nie muskariniese reseptore nie. Voordele is dat dit bruikbaar is by lang- of korttermynbehandeling van allergiese rinitis.  Aangesien histamien geen rol by verkouerinitisnie speel nie, maar wel bradikinien, help hierdie middels nie om verkouerinitis op te klaar nie.

Wanneer is kortikosteroïede, anti-allergiese middels, mesna en normale soutoplossing bruikbaar en hoe word dit toegedien?

• Die gebruik van Anti-allergiese middels is baie effektief by die profilaktiese behandeling van allergiese rhinitis en word toegedien in ‘n neussproei vorm.
• Kortikosteroïde word gebruik teen allergiese rinitis en is in die vorm van ‘n neussproei.
• Mesna word gebruik wanneer die nasale sekrete taai is by rinoree en rhinitis en is in die vorm van ʼn topikale mesna (neursproei).
• Normale soutoplossing is die eerste keuse vir mucus verdunning, stoom inhalasies is effektief.

Give your own definition of COPD.

• Chronic obstructive pulmonary disease is an inclusive term for chronic bronchitis, bronchial asthma and emphysema with the progressive limitation of airflow. This involves constriction of the airways and result in discomfort and makes it difficult to breathe.

Beskryf kortliks die voorgestelde etiologie en patofisiologie van chroniese brongitis en emfiseem.

• Chronic bronchitis: Non-specific obstructive airway disease with increased mucus productions and decreased mucosal clearance. Also the appearance of structural changes in the bronchial wall, frequent bacterial airway infections and chronic cough due to sticky mucus.
• Emphysema: This develops usually due to smoking and other irritants (air pollution, chemical fumes). Causes irreversible removal of respiratory bronchiole and alveoli due to structural damage which leads to decreased capillary blood vessel gas exchange.

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

• Stop smoking
• Bacterial infections – Immunization against influenza, wide spectrum antibiotics (tetracyclines, erythromycin)
• Airflow obstruction – Bronchodilators
• Mucus secretion – Dilute mucus (steam and rehydration)
• Hypoxia – Oxygen inhalations
• Poor lung capacity – Regular light to moderate exercise

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

• In asthma a person’s airways become inflamed and ipratropium does not have anti-inflammatory effects. Ipratropium is an anticholinergic agent which inhibits vagus-mediated bronchoconstriction which is more suitable for chronic bronchitis.

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

• Theophylline improves contractility of skeletal muscle and reverse fatigue of the diaphragm in patients with COPD. This effect improves the ventilatory response to hypoxia and to diminish dyspnea even in patients with irreversible airflow obstruction.

What is the role of oxygen therapy in COPD.

• This will increase oxygen levels in the lungs and blood circulation that will help improve the shortness of breath (dyspnea) and hypoxia.

Wat beteken die term “endotelium-afhanklike” vasodilatasie vir jou? Verduidelik.

The term refers to the action of the increase of intracellular calcium levels in endothelial cells, leading to NO synthesis and NO then diffuses to the vascular smooth muscle leading to the effect of vasodilatation/vasorelaxation.

As ons praat van die NOS-ensieme, wat beteken “konstitueel” en “geïnduseerde” ensieme, en wat is die patologiese en fisiologiese implikasies hiervan?

Constitutive enzymes are synthesized at a constant level and also constant amounts. These enzymes are always produced whether or not a suitable substrate is present or regardless of its metabolic state and these enzymes are regulated by calcium.

Inducible enzymes are not regulated by calcium, the presence of an inducer leads to an increase in gene expression. When substrates are added, it results in a major increase of this enzyme leading to iNOS accumulation and produces a great amount of NO.

Verduidelik hoe NO tot die noodlottige patologie van septiese skok bydra.

Endotoxin components from the bacterial wall along with endogenously generated tumor necrosis factor and other cytokines induce the synthesis of iNOS in macrophages, neutrophils, T cells as well as hepatocytes, smooth muscle cells, endothelial cells and fibroblasts. This widespread generation on NO results in exaggerated hypotension, shock and in some case death.

Watter outakoïede se meganisme van werking berus op effekte op die guanilielsiklase-cGMP-stelsel?

Nitric Oxide (NO)

NO kan vir die sel toksies wees.  Watter maniere het die liggaam om hierdie nadelige effek van NO teen te werk?

NO can react with hemoglobin which leads to S-nitrosylation of hemoglobin, resulting in the transport of nitric oxide throughout the vasculature.

NO can be inactivated by reacting with O2 to form nitrogen dioxide.

NO can also react with heme and hemoproteins so that NO can be oxidized to nitrate.

Noem ‘n manier hoe NO pro-inflammatories kan optree.  Gee voorbeelde waar dit voor- of nadele sal hê

NO is considered as a pro-inflammatory mediator that induces inflammation in response to abnormal situations meaning that NO helps to regulate the immune system.

Advantages: NO appears to play an important protective role in the body via immune cell function. When foreign antigens are present, TH1 cells respond by synthesizing NO and the importance of this action is demonstrated by the impaired protective response to injected parasites in animal models after inhibition of iNOS.

Disadvantages: Prolonged or excessive NO production can exacerbate tissue injury in both acute and chronic inflammatory conditions.

In watter moontlike neurologiese en psigiese siektes is NO betrokke?

Parkinson’s disease, stroke, amyotrophic lateral sclerosis.

In watter siektetoestande is angiotensinogeenvlakke verhoog?  Wat is die implikasies hiervan?

Increased levels of angiotensinogen are associated with Hypertension. High levels of angiotensinogen in the plasma can lead to elevated blood pressure and the body will retain too much fluid. This can also cause the heart to work harder and to grow, can result in heart failure. The synthesis of angiotensinogen is increased by estrogens, thyroid hormones, corticosteroids, ANG II and it is also elevated during pregnancy or when taking estrogen contraceptives.

Wat is die rede daarvoor dat middels wat die angiotensienstelsel deur werking op angiotensienreseptore rem, minder newe-effekte het as die wat AOE rem?

Angiotensin receptor blockers are similar to ACE inhibitors, but they have a lower incidence of cough. The blocking of the angiotensin I receptors, the metabolism of Bradykinin to inactive metabolites is not affected which result in the lower incident of dry cough.

Op watter wyse het AOE-remmers ‘n tweevoudige meganisme van werking by die behandeling van hipertensie?

ACE inhibitors inhibit the conversion of ANG I to ANG II which is useful in the treatment of hypertension and it also inhibits the degradation of other substances like bradykinin, substance P and enkephalins. This helps with vasodilatation and decreases peripheral resistance and therefore lowers the blood pressure.

Op watter tipe angiotensienreseptore werk losartan en soortgelyke middels?  Het hulle enige effekte, direk of indirek, op ander angiotensien II-reseptore?

Losartan and Valsartan are specific competitive antagonists at the AT1 receptors. These drugs are AT1 selective and prolonged treatment will result in the disinhibit of renin release which leads to an increase in the circulating ANG II levels. There might be an increased stimulation of the AT2 receptors which have a indirect effect on AT2 receptors.

Wat is die fisiologiese effekte van kiniene op arterieë en vene?  Speel ander outakoïede ‘n rol in hierdie werking?  Verduidelik.

Kinins are known as potent vasodilator peptides. The vasodilatation may be mediated by the release release of NO or vasodilator prostaglandins like PGE2 and PGI2. Other effects of bradykinin include increased release of cAMP, IP3, DAG and also increased capillary permeabilty. All of these contribute to the vasodilatory effects of kinins.

Watter reseptor is waarskynlik die mees betrokke in die klinies-belangrike effekte van kiniene?

Bradykinin 2 receptors (B2 receptor)

Op watter wyse is natriuretiese peptiede moontlik effektief in die behandeling van hipertensie, asook kongestiewe hartversaking?

The effects of ANP and BNP include vasodilatation, increased Na excretion and GFR, decreased renin secretion, aldosterone mechanism (less Na reabsorption) and inhibits angiotensin II. Because of the vasodilatation and natriuresis, these peptides have been investigated for the treatment of congestive heart failure.

Wat is neprilisien en wat is die rasionaal om sy aktiwiteit te inhibeer by die behandeling van hartversaking. Kan jy die middel noem wat sodanig gebruik word. Verwys ook na leereenheid 1 waar julle ook met die spesifieke middel te doen gekry het.

Neprilysin is a neutral endopeptidase (enzyme) that metabolizes ANP and BNP. When this enzyme is inhibited, it results in increased levels of circulating ANP and BNP which leads to increased natriuresis, diuresis and vasodilatation as well as a compensatory increase in renin secretion and plasma ANG II. Due to the increased levels of ANG II, these drugs are not effective as monotherapy in the treatment of heart failure, but in combination with ACE inhibitors. The drug that is used to inhibit neprilysin is Sacubitril.

Gee voorbeelde van endotelium-afgeleide vasodilatore en vasokonstriktore.

Vasodilators: CGRP, VIP, Substance P

Vasoconstrictors: NPY

Migraine involves the trigeminal sensory nerve distribution to intra-cranial arteries. These nerves stimulate the release of peptide neurotransmitters which leads to vasodilatation. The peptide neurotransmitters are calcitonin gene-related peptide (CGRP), which is a potent vasodilator, and also substance P and neurokinin A. This action of the neuropeptides may be the immediate cause of a pain response. Characteristics of migraine include aggravation by routine physical activity, moderate or severe intensity, association with nausea and usually it lasts about 4 to 72 hours.

Treatment of migraine

• Ergot Alkaloids - The action of Ergot derivatives specifically relates to the vasoconstriction effects. They have affinity for a wide range of receptors including dopaminergic, serotonergic and adrenergic receptors (alpha), with cause contraction of the smooth muscles. Drug examples are ergotamine, dihydroergotamine and methysergide.

• Triptans - These drugs are currently the first line therapy for acute migraine having a high affinity for 5-HT 1D and 5-HT 1B receptors. The mechanism of action for triptans is the constriction of dilated cranial blood vessels and to inhibit the release of the sensory neuropeptides ( which causes the dilation). Drug examples are sumatriptan, naratriptan and rizatriptan.

• Anti-inflammatory analgesics can be used to control the pain, such as aspirin and ibuprofen.

• Agents for prophylaxis of migraine include beta-blockers like propranolol, antidepressants such as amitriptyline, calcium channel blockers like flunarizine and also anticonvulsants like valproic acid.

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

Cystic fibrosis is a genetic defect that can lead to a decrease in secretions in various organs. The most prominent manifestation and problematic symptom is in the airways. The airway has exceptionally thick and sticky mucus secretions which provides an excellent environment for bacterial infections. The repeated infections cause continuous chemotaxis of neutrophils which then leads to deposits of DNA (this occurs during disintegration),which makes the mucus even stickier. The mucus then becomes virtually impossible to clear and a vicious circle of sticky mucus and further infections results.

Dornase alfa (rhDNase I) hydrolyses extra-cellular DNA from the neutrophils in the bronchial mucus, which increase it`s liquidity drastically. It is related to the natural enzyme doexyribonuclease I (DNase I) which is normally produced by the pancreas and salivary glands.

• 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 also known as hyaline membrane disease.  The surface-active material which covers the respiratory unit of the airways is formed only in the last weeks of pregnancy.  When babies are born prematurely, this surface-active material has not yet formed, resulting in disrupted gas exchange and also the possibility that the lungs may collapse.  Treatment must follow rapidly in order to save the life of the premature baby.

General treatment strategies include oxygen to ensure oxygenation, ventilation used for positive pressure and drugs: exogenous sufactants (beractant and poractant alfa).

Cortisone: Boosts endogenous surfactant production and can be administered prophylactically.

Exogenous surfactants: Increases the lung surfactant.

• 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).  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?

Neonatal apnoea occurs when the respiratory centre in the medulla of the premature baby has not yet developed sufficiently to stimulate continuous breathing.  The breathing centre is, therefore, still insensitive to the stimulating effect of carbon dioxide.  Apnoea has a duration, typically, of longer than 15 seconds and is accompanied by bradycardia. Repeated episodes of apnoea with hypoxia can eventually lead to neural damage.

Methylxanthines, especially caffeine and theophylline, stimulate the central nervous system and intravenous administrations of these drugs usually help to solve the problem.  Therapy is however, usually discontinued as soon as possible – usually after a few weeks in intensive care.  The neonate then also receives oxygen therapy and the oxygen levels in the blood are continuously monitored.

• What are the general causes of rhinitis and rhinorrhoea?

1.  Rhinitis associasted with colds and flue
2. Mucosal Rhinitis (associated with sinusitis)
3. Allergic rhinitis (allergen exposure, IgE mediated inflammation)
4. Non-allergic rhinitis (physiological response due to stimuli such as cold, heat or smoke)

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

1. Alpha1-agonists eg: naphazoline
2. Antihistamines eg: loratadine
3. Corticosteroids eg: budesonide
4. Mast cell stabilisers eg: ketotifen
5. Mucolytics eg: mesna
6. Antibiotics eg: neomycin
7. Diverse drugs eg: normal saline

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

MOA: The decongestants are alpha-adrenoreceptor sympathomimmetics, which causes vasoconstriction, which opposes vasodilation; this will reduce the nasal airway resistance and thus facilitate nose breathing.

Duration of action: Decongestants provide rapid relief that my last up to 12 hours, but may only be used 5-7 days.

Decongestants are usually administered topically via metered-dose sprays (which is the safest).

• What is rhinitis medicamentosa?  How is it treated?

Rhinitis medicamentosa is a condition which develops if topical decongestants are used for a period longer than 7 days. This conditions happens when there is an overstimulation of the alpha receptors in the nasal mucosa, which leads to the drying out of the mucosal  tissue. This leads to a blocked nose which is difficult to treat with medication. It can however be treated by cortisone nasal sprays.

• 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 can be used for non-allergic rhinorrhoea, because it reduces the inflammation in the nose and in effect treats the symptom.

Second generation antihistamines can be used to treat allergic rhinitis. This medicine acts by inhibiting mast cell release of histamine and some other mediators of inflammation.

The advantages of the second generation of antihistamines are that they have little to no CNS distribution and in effect have a low incidence of patients who experience sedation and anticholinergic side effects.  

Antihistamines should not be used to relieve cold rhinitis, because some symptoms caused by body`s responses are not related to histamine production, in effect antihistamines will have no effect. In other words histamine is not the major cause of a runny nose. (Bradykinin plays a role.)

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

*Corticosteroids: These drugs are valid for the use of allergic rhinitis and is administered topically in the form of a nasal spray.

*Anti-allergic drugs: These drugs are valid for the prophylactic treatment of allergic rhinitis and is administered topically in the form of a nasal spray.

*Mesna: This drug is valid when the nasal secretion is sticky as it helps to make the mucus more liquid. It is administered topically in the form of a nasal spray.

*Normal salt solution: This drug is valid for the use of humidifying the dry  and inflamed mucous membranes of the nose during colds, dry weather, allergy (hay fever), nose bleeding, overuse of decongestants and other irritations. This drug is administered topically in the form of nasal drops.

Pathology of Migraines

Migraines usually occur at the reduction of blood flow and occurs during cerebral hyperperfusion in the headache phase. Migraine is viewed as a disorder that influences cerebral hemodynamics. It can be said that blood flow changes do not always correlate with the symptoms seen in a migraine attack. Multiple factors influences a migraine: chemical, metabolic, neurogenic and myogenic. https://scite.ai/reports/10.1097/00002508-199009000-00011

Vascular pathology is often associated with migraines, because endothelial dysfunction may be an early marker for migraines.

Larrosa-Campo D, Ramón-Carbajo C, Álvarez-Escudero R, et al. [Arterial pathology in migraine: endothelial dysfunction and structural changes in the brain and systemic vasculature]. Revista de Neurologia. 2015 Oct;61(7):313-322. PMID: 26411276.

Current treatment and mechanism of action

• Ergot alkaloids: If it is an acute migraine= ergotamide, if migraine prophylaxis=methysergideInduces vasoconstriction which is long-lasting.
• Autocoids:migraine prophylaxis=flunarizine.

Aktiwiteit

Dropbox opsomming

1. Teoliffien is ‘n verligter by asma en profilakse nie COLS.
2. Inhibeer PDE wat verhooging in cAMP en cGMP wat brogodilatasie en gladdespier ontspanning tot gevolg het. Beta 2 agoniste is G-protien gekoppel wat cAMP stimuleer wat lei to brongodilatasie en ontspanning van gladdespier Anti-muskariene keer die binding van ACH sodat galddespiere ontspan en brongodilatasie voorkom. Beta 2 agonis stimuleer AdenielSiklase verhoog cAMP in gladdespier = brongodilatasie. Inhalasie of Nebulizer. Salbutamol word gebruik vir chroniese asma lig-matig. Daaglikse kort-asem met fluidgeluid asook Status asmatikus-nebulisasie. Salmeterol  langer duur voor hy werk = nie verligter nie = akute brongokonstruksie. Nie-oefening Asma- neem te lank om te werk voor oefening 10-15 min. Formeterol vinniger aanvang van werking. Verligter by akute brongokonstruksie. Oefening-induseerde asma. Kortwerkend Beta 2 agoniste behandel akute asma en langwerkende agoniste behandel chroniese asma, profilakse en nagtelike asma.
3. Metielxanitien het ‘n effek op plasma opruimingstempo tempo is die vinnigste in kinders en stadig in neonate en het ook ‘n effek op metabolisme in die lewer. SSS verhoog wakkerheid, konvulsies en slapeloosheid en skeletspiere het positiewe effekte versterk kontraksie van diafragma wat suurstof verminder en asmen nood veroorsaak.en verbeter ventilasie respons verlaag hipoksie een dispnee in KOLS pasiënte.
4. Teofillien word gemetaboliseer in die lewer deur sitochroom P450 sodra die ensiem geinhibeer word verlaag die metabolisme van teofillien, plasma vlakke verhoog en toksisiteit van teofillien volg. Die terapetiese indeks is klein meer  as 20ug/ml veroorsaak geweldig baie newe-effekte soos; naarheid, diarree, braking, slapeloosheid hoofpyn ens. Meer as 40ug/ml lei to konvulsies en hart disritmië. Sitochroom P450 word geinduseer deur and geneesmiddel interaksies wat die ensiem Aktiwiteit verbeter.
5. Toediening van eofillien aerosol inhalasie intra-veneus(iv) en oral. Bevorder die werkingsduur van 8-12 ure.
6. Die teofillien se interaskie met eritromisien inhibeer die metabolisme van teofillien. Die Sitochroom CYP450 inhibeer die metabolisme van teofillien en verhoog die plasma vlakke en toksisiteit van teofillien bevorder. Teofillien het ‘n klein terapeutiese indeks sodra die metabolisme van teofillien geinhibeer vererger die effekte van teofillien wat lei tot toksisiteit dit sluit in oormatige SSS stimulasie (konvulsies by hoe vakke) en kardiale disritmiee. Ek sal nie eritromisien-antibiotika eerder gee vir die pasiënt nie.Siproflokasien inhibeer die metabolisme van teofillien. Die siproflokasien word gebruik om unrienweginfeskie te behandel, hierdie geneesmiddel stop die groei van bakteriële infeksies. Siproflokasien se newe-effekte is sooibrand, goed so ons gaan siproflokasien versigtig gebruik omrede die pasiënt reeds kla van sooibrand.

Blog 3.5

Leereenheid 3.5

1. Genetiese metabolise siekte wat lei tot ‘n verlaagde sekeresie van verskeie organe. Dornase-alfa hidroliseer ekstrasellulêre DNS vanaf neotrofiele tot by die brongiale mucus waar dit die mucus se vloeibaarheid verbeter.
2. Kom voor by premutare babas waar  ‘n oppervlak aktiewe stof wat die lugweë bedek is noodsaaklik vir gaswisseling en vorm kort voor geboorte nog nie gevorm het nie. Longe kan plat vale n lei tot die dood.

Algemene behandelingstrategie is intensiewe moniteringvan respiratoriese en sirkulatoriese status. Kortisoon en eksogene surfaktante help om die longsurfaktante aan te vul. Verlaag die mortalilteit en suurstofbehoefte.

3. Suurstofterapie verseker osksinering, kontunie positiewe druk (ventalators) verbeter respirasie en hou alvieole oop om kollabering te voorkom. Regulering van alviole parsiële suurstofvlakke noukeurig. Keer of verhoed hipoksie. Oormatige suurstof oor ‘n te langtydperk lei tot suurstoftoksisiteit. Paradosaal veroorsaak suurstof- toksisiteit wat lei tot die dood,verminderde gaswisseling en hipoksie.
4. Asmelhalingsentrum in die brein is nog nie so goed ontwikkel in die neonate of premature babas nie voordurende stumilering van asemhaling vind nie plaas nie. Metielxantiene stimuleer die SSS en IV toediening. Teofillien en kaffiene.

Blog Aktiwiteit 3.2

LE 3.2

1. COLS- Chroniese obstruktiewe siektes beskryf verskillende kombinasies en grade van drie obstruktiewe lugwegtoestande, naamlik brongiale asma, chroniese brongitis en emfiseem.  Hierdie toestande beperk pulmonêre lugvloei en gaswisseling en kan dus lewensgehalte verlaag deurdat dit slaapsteurnisse veroorsaak, die vermoë tot fisiese aktiwiteit verminder en met akute aanvalle tot angs, hipoksie en selfs die dood kan lei.

3. Rookgewoonte:

Staking van die rookgewoonte is uiters belangrik en hiersonder kan progressie nie verhoed word nie.  Psigoterapie, konsultasie en bemoediging (eerder positief as waar­skuwend), asook ondersteuning met moontlik ander hulpmiddels om die gewoonte te staak is belangrik.  Daar is egter omstredenheid oor die effektiwiteit van nikotienbevattende middels om die staking van die rookgewoonte te ondersteun.

Bakteriële infeksie:

Profilakties kan jaarlikse immunisering teen influenza (baie effektief) eneenmalige immunisering teen pneumokokke (minder effektief) oorweeg word.  Breëspektrum-antibiotika (tetrasikliene, ko-trimoksasool, amoksisillien, ampisillien of eritromisien) kan soos nodig teen veral pneumokokke en Haemofilus influenza gebruik word.

Lugvloei-obstruksie:

Lugvloei-obstruksie kan behandel word met behulp van geneesmiddels soos vir brongiale asma.  Die geneesmiddelkeuses is egter ietwat anders, soos hieronder bespreek. Die gebruik van 'n voorkamer saam met aërosole en gereelde lugvloei­monitering deur middel van 'n piekvloeimeter hou heelwat voordele in.

Sekrete:

Rehidrering (voldoende inname van vloeistowwe) en gereelde stoom (bv. idifiseerer snags) verdun die mukus en bevorder mukusopruiming.

Hipoksie:

In erge grade van COLS verbeter 18-24 ure/dag O₂-inhalasieterapie die morbiditeit en mortaliteit drasties.  Dit word dus sterk aanbeveel in gevalle van volgehoue hipoksie (verskeie tipes draagbare O₂-houers is beskikbaar). Sommige pasiënte benodig O₂‑inhalasieterapie slegs met oefening of tydens slaap.

Swak longkapasiteite:

Matige en gereelde oefening verbeter longkapasiteite en lewensgehalte, maar oet met omsigtigheid hanteer word waar hartkomplikasies reeds aanwesig is.

4. Anticholinergiese terapie (ipratropium-inhalasie) hedendaags verkies as eerste-linie middel by die behandeling van chroniese brongitis omrede dit ‘n M3 antagoniste in lugweg is en blok die binding van ACH, lei tot brongodilatasie en verlaag mucus produksie. Aangesien die vagusrefleks ’n tipiese gevolg van die stimulasie van irritantreseptore in die lugweë het.
5. Teofillien het veral die voordeel dat dit diafragmakontraktiliteit verbeter en diafragma-uitputting verminder, kardiale kontraktiliteit verbeter, pulmonale weerstand verlaag, mukosiliêre opruiming verbeter en die ventilatoriese respons op hipoksemie verbeter.
6. Die suurstof terapie help met die behandeling van hipoksie.

1. Vaskulêre veranderinge erge hoofpyn sonder of met aura 20% omkeerbare fokale neurologiese simptome 5-10min voor begin van hoofpyn ontwikkel duur vir minder as 60min, 80% is erge kloppende hoofpyne net aan die een kant van kop. Visiesteurnisse, naarheid, braking en anoreksia.
2. Serotonien is 'n chemikalie wat nodig is vir kommunikasie tussen senuweeselle. Dit kan vernouing van bloedvate regdeur die liggaam veroorsaak. Wanneer serotonienvlakke verander, is die gevolg vir sommige 'n migraine. Aktivering van 5-HT1B reseptore veroorsaak vasokonstriksie van kraniale arteries wat pynlik verwyd tydens akute migraine. Aktiveer 5HT1D reseptore op presinaptiese trigeminale senuwee-eindes om neuro-aktiewe vasopeptied vrystelling te inhibeer en blok die transmissie van pynimpulse na brein. Word gebruik na eerste hoofpyn.
3. Ergotamien 5HT1D gedeeltilke agonis wat direkte vasokonstriksie veral van intrakraniale arteries veroorsaak. Ergotamien word nie saam met triptane gebruik nie vererger hoofpyn.
4. Newe effekte van ergotamine naarheid en braking, diarree, hallusinasie en verwaring, gangrene, retroperitoneale fibrose, tagikardie/bradikardie , angina pyn, terugslaghoofpyn gereelde gebruik.

Kontra Indikasie Koronêre-serebrale en perifere vaskulêre siektes, KI Hipertensie , IK Swangerskap en IK Kombinasie met triptane=hoofpyn.

6. Migrane Profilakse

Voorsorgmaatreëls is as volg; rus in stil, donker kamer tydens aanval, neem medikasie met eerste gewaarwording van migraine, selfs aspirien en parasetamol kan verligting bring indien vroegtydig gebruik, vermy analgetika oorgebruik; terugslag hoofpyne kan volg, vermy faktore wat aanval uitlok bv kossoorte,ligt ens. Profilakse kan tot 6 weke neem vir maksimum effek, nie im alle migrainelyers effektief nie. Leefstyl veranderinge kan help bv. Verlaag stress.

1. Kolgesien by die behandeling van jigartritis inhibeer mikro-tubuli en spoelvorming in makrogage en leukosiete. Inhibeer chemotakse (beweeging van leukosiete na areas van inflammasie). Verlaag metabolisme van leukosiete verminder suurvorming. Verhoog PH (agv uriensuurkristalle). Inhibeer vorming van ITB 4 en IL-1. Behandel akute jig.
2. SVK –ongemak, braking, naarheid, diarree, maagbloedings, lewer en nierskade, beenmurgonderdrukking, perifere neuritis, alopesie (haarverlies)

KI Swangerskap en KI Nier en lewerinkorting. Doseering van akute aanval 0.5-1mg dadelik, gevolg deur 0.5mg elke 6 ure tot pynverligting of ongemak. Maksimum is 2.5mg in eerste 24h, nie meer as 6mg oor 4 dae nie asook kursus mag nie binne 3dae herhaal word nie. Chronies aanval 0.5mg kolgisien 1-2keer per dag tot uraatverlagende middels toegedien kan word.

3. Middels vir die gebruik vir akute jigaanval.

4. Probenesied is ‘n urikosuriesemiddels wat uriensuur ekskresie laat toe neem.
5. Allopurinol is uriensuursinteseremmers-Xantien-oksidase inhibeerders Onomkeerbare inhibeerders, verminder die omskakeling van xantien na uriensuur = verlaag uriensuurproduksie, verhoog dus [xantien] en [hipoxantien] =Meer wateroplosbaar = beter uitskeiding, verlaag [uriensuur] en behandel chroniese Jig. Newe- effekte Hipersensitiwiteitsreaksie 021(veluitsalg,Urtikaria), SVK –effekte naarhied, braking en hoofpyn. Voorsorgmaatreëls drink baie water, pas diet aan; verminder proteïene, aspirien vererger akute jig, vermy urikosuriese middels in akute jig en gebruik urienalkaliniseerders (bv Citro-soda).

Leergedeelte 2.6

Dropbox Aktiwiteit

Anelia du Plessis

31600298

1. Vir ligte en middelmatige pyn, toon geen effek op plaatjie aggregasie agv ‘n swak COX1 en COX2 inhibeerder, COX3 inhibeerder aktivering van dalende serotonergiese analgetiese bane. Parasetamol is analgeties asook antipiretiese effekte maar nie anti-inflammatoriese effekte nie waar aspirien anti-inflammatoriese, analgetiese,antipiretiese en anti-plaatjies effekte induseer.
2. Ligte tot middelmatige pyn, veilig gebruik in kinders, swangerskap, asma, jig, peptise ulkusse en hemofilie pasiënte, antipireties, geen invloed op plaatjieklewing nie en geen invloed op uriensuuruitskeiding. ‘n Voorkeurmiddel van pyn en koors is akute pyn 325-1000mg (1-2 tablette) 4 maal per dag, Chroniese pyn minder as 2g (4tablette) per 24h. Nie meer as 4g in 24h nie.
3. Newe-effekte van parasetamol sluit in: veluitslag, urtikaria, chroniese gebruik van 2g/d lei tot parasetamol vergiftiging, toksisiteit verhoog indien parasetamol saam analgetika geneem word en wees versigtig in alkoliste dosisse kan lewertoksies wees, lewer en niersaiektes en anemie.
4. Akute parasetamol toksisiteit

Akute pyn: 325mg – 1000mg 4 maal per dag. Nie meer as 4 g in 24 uur (akute lewerversaking, veluitslae = Stevens-Johnson). Oordosering veroorsaak fatale hepatotoksiteit. Toksiese dosisse= 10-15g/ 20-30 tablette. Parasetamolvergiftiging kom voor wanneer die lewer ensieme wat konjugasie van parasetamol kataliseer verstadig en toksisiese NAPQI vorm. NAPQI word gedeaktiveer deur glutatioon maar sodra glutatioon vlakke uitgeput is veroorsaak NAPQI nekrose in die lewer en nierbuise. Tekens en simptome kan eers binne 1-2 dae waargeneem word simptome soos Naarheid en braking, abdominale pyn, verlaagde eetlus, moeg en kragteloos. Renale inkorting en hepatoksisiteit asook regter subkostale pyn, teer lewer, geelsug, lewerselnekrose en die  dood. Behandeling van akute parasetamol toksisiteit is onmiddellike aanvulling van –SH-groepe om glutatioon in lewer aan te vul en lewerselnekrose te verhoed. N-asetielsisteïen (Parvolex®) binne 8-12 uur IV toegedien. Aanvangsdosis: 150mg/kg in 200ml 5% glukose oor 15 minute, daarna 50 mg/kg in 500 ml 5% glukose oor 4 ure en daarna 100 mg/kg in 1 000 ml 5% glukose oor 16 ure. Orale behadeling: Asetielsisteïen bv Solmucol en ACC wat slymproduksie verminder 140mg/kg kan toegedien word. Karbosisteïen bv Mucosirop en Flemex 150mg/kg. Binne 1 uur na vergiftiging:Induseer braking, doen maagspoeling, gee geaktiveerde koolstof as IV behandeling gebruik word.  Behandeling slegs effektief binne 10 ure van vergiftiging

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 is used

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-acting drugs (4 to 6 hours), e.g. ephedrine, phenylephrine, propylhexedrine, naphazoline and tetrahydrozoline;
• intermediary acting drugs (8 to 10 hours), e.g. xylometazoline;
• long-acting drugs (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/lavange

• 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.

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

Angiotensinogen is increased in hypertension and heart failure. Increased levels of angiotensinogen increases the amount of angiotensin I that can be converted into angiotensin II, thus decreasing the amount of bradykinin in the body, which causes an increase in vasoconstriction. This leads to hypertension, retention of fluid into the urinary tract and ventricular hypertophy.

Why do drugs which inhibit the angiotensinogen system by acting on angiotensin receptors have fewer side effects than those that inhibit ACE?

Drugs that inhibit the angiotensinogen system have a more complete blockage of the angiotensin system than ACE inhibitors, thus there is no increase in bradykinin, which leads to fewer side effects. The angiotensin blockers are also more selective than the non-selective ACE inhibitors, thus it will have less effects since the non-selective ACE inhibitors.

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

ACE inhibitors first inhibits the conversion of angiotensin I to angiotensin II, which increases bradykinin, which causes vasodilation and thus a decrease in blood pressure. It also decreases peripheral ventricular resistance which leads to a decrease in 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?

Losartan acts on the agiotensin II receptors by blocking it, it also has action on the angiotensin I receptors.

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

Kinins are potent vasodilators. It increases cAMP; IP3, DAG, NO, PG and capilliary permeability. Prostaglandins also play a role here.

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

Bradykinin receptors (1&2)

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

• VASODILATOR
• increase glomerular filtration
• deacrese renin secretion & Aldosterone mechanism (↓Na reabsorption) & inhibit angiotensin II.
• ↓ effect of Angiotensin and aldosterone and Na secretion.

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.

it is a neutral endopeptidase which is responisble the breakdown of natiuretic peptides in the kidney liver and lungs.

inhibition of this increases circulating levels of ANP and BNP and thus causes natriuresis and diureses. (Sacubitril)

Give examples of endothelium-derived vasodilators and vasoconstrictors.

vasodilators: PGI₂ & NO

vasoconstrictors: Endothelin - ET₁, ET₂, ET₃

An acute migraine is due to rapid vasodilation which causes pain. Vasoconstrictors combat this, thus the pain caused by the vasodilation goes away.

Serotonin 1D/B receptor agonists are vasoconstrictors (Sumatriptan, Naratriptan, Rizatriptan) in the intracranial cavity and combats the pain in a migraine

Uteroselective ergovine causes vasoconstriction and is used as a migraine prophylaxis

Ergotamine causes vasoconstriction and is used in acute migraines and cluster headaches.

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

Cystic fibrosis is a genetic metabolic disease with reduced DNase I concentration that cause a reduction in secretions in various organs. The airways display the worst symptoms. The mucus becomes so thick and sticky, that it causes recurrent bacterial infections. The body does not have the ability to remove this mucus.

Dornase alpha (which is rhDNase I) inhalations hydrolyze the proteins in bronchial mucus and makes the mucus more fluid so that it can be more easily removed.

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

Also called hyaline membrane disease. It is found in premature babies when the surfactant that covers a normal person's airways which are responsible for gas exchange are not present (this surfactant is produced just before birth and are therefore not present in a premature baby). The lungs can fall flat (atelectasis) which is fatal.

Treatment strategies:

Monitoring respiratory and circulatory function, is essential.

Oxygen ensures oxygenation (but do not use too long because can cause retinal damage and blindness)

Ventilation ensures positive pressure

Exogenous surfactants such as beractant or poractant alpha which provides surfactant so that gas exchange can take place an the lungs don't collapse.

Corticosteroids such as betamethasone administered systemically (orally) prophylactically to the mother before labour to induce the surfactant reproduction of the baby/initiate the baby's surfactant reproduction.

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

It provides oxygenation which makes up for the impeding gas exchange.

Retinal damage that cause blindness.

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

The respiratory center in the medulla is not yet fully developed to stimulate continuous breathing in neonates and premature babies. Apnoea together with bradycardia happens longer than 15 seconds and repeatedly. This cause hypoxia and neural damage.

Methylxanthines (theophylline and caffeine IV for weeks) stimulate the CNS.

• What are the general causes of rhinitis and rhinorrhoea?

Allergies, colds and flue, cold air, physical damage, chemical or drug damage.

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

First generation antihistamines: diphenhydramine, promethazine, chlorpheniramine, brompheniramine

Alpha 1 agonist/decongestants: phenylephrine, ephedrine, phenylpropanolamine, naphazoline, xylometazoline, oxymetazoline

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

Ephedrine, pseudoephedrine and propylhexidrine are non-selective for adrenoceptors and thus stimulate alpha and beta adrenoceptors with a potent indirect action and mixed action.

Phenylephrine is direct acting.

Naphazoline, xylometazoline and oxymetazoline are imidazole derivatives with mixed action.

They are administered as nasal sprays, gels/jellies, drops and inhalations.

Short acting (4-6 hours): ephedrine, phenylephrine, naphazoline

Intermediate acting (8-10 hours): xylometazoline

Long acting (more than 12 hours): oxymetazoline

• What is rhinitis medicamentosa?  How is it treated?

It happens when decongestants/alpha 1 agonist are used chronically.

The permanent vasoconstriction of nasal capillaries and reduced blood supply to the nasal mucosa/nasal walls, damages the nasal mucosa which cause permanent swelling and inflammation of the nasal walls. Alpha 1 receptor deregulation also happens which leads to the receptors not acting on alpha 1 stimuli. Tachyphylaxis (depletion of l-NA) also occur.

Treatment: Corticosteroid/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 only relieve rhinorrhoea caused by colds. They are multipotent antagonists which also antagonizes muscarinic receptors and thus reduce mucus secretions/mucus production in the upper and lower airways.

Second generation antihistamines only relieve allergic rhinitis. They only antagonize histamine 1 receptors which has an anti-inflammatory effect. The second generation drugs to not cause sedation or reduced concentration and can be used in prophylactic/chronic treatment of allergic rhinitis.

They should not be used to relieve cold rhinitis because they do not have an effect on bradykinin receptors (bradykinin and not histamine are released during colds and thus bradykinin receptors and not histamine receptors should be blocked).

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

Corticosteroids (nasal drops/topical): allergic rhinitis, inflammatory rhinitis, nasal polyps, reversal of rhinitis medicamentosa/privinism

Anti-allergic drugs/mast cell stabilizers (topical): prophylaxis of allergic rhinitis

Mesna (topical/nasal sprays): diluting sticky nasal mucus

Normal salt saline solution (topical/nasal sprays): nasal lavage to dilute mucus caused by sinusitis.

• Give your own definition of COPD.

COPD consist of different degrees and combinations of bronchial asthma, chronic bronchitis and emphysema.

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

Chronic bronchitis:

Aetiology is unknown (idiopathic).

It is a non-specific obstructive disease where there are an increase in mucus production/secretion and a decrease in mucus clearance. The bronchial walls undergo structural changes, frequent respiratory bacterial infections occur and a chronic cough due to sticky mucous occur.

Emphysema:

Aetiology is smoking, irritants and those who are susceptible because of an alpha 1 antitrypsin deficiency.

It is the irreversible dilation of respiratory bronchioles and alveoli due to structural changes. Air gets trapped in the lungs and are exhaled with difficulty. There are also a decrease in capillary blood vessels which further impedes gas exchange.

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

Anticholinergics: Ipratropium and tiotropium (or long acting: glycopyronium bromide)

Bete 2 stimulants and/or slow release theophylline

Corticosteroids sometime used but not usually well tolerated

Oxygen therapy

Acute illness: hospitalization, antibiotics, physiotherrapy

Cessation of smoking

Bacterial infections: yearly influenza immunization or broad spectrum antibiotics (tetracyclines, ampicillin, amoxicillin, erythromycin, cotrimoxazole)

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

Chronic bronchitis is due to irritants that stimulate the vagus reflex which cause an overactive parasympathetic nervous system while asthma is due to sympathetic and parasympathetic effects. Ipratropium which is an anticholinergic drug and parasympatholytic will thus be more effective in bronchitis and not in bronchial asthma as although some effect will be seen because of inhibition of the parasympathetic nerve system, the sympathetic nervous sytem will be unopposed thus asthma symptoms will not be entirely reduced by ipratropium.

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

It strengthens the contraction of diaphragm skeletal muscles which improves the ventilation response/ventilation capacity, reduce the hypoxia and reduce the dyspnea associated with COPD.

• What is the role of oxygen therapy in COPD?

It reduce the symptom of hypoxia associated with COPD.

Rationale for using Fluvoxamine (=SSRI) in the treatment of Covid-19 patients:

Fluvoxamine binds to the sigma-1 receptor and stimulates this receptor which is found in immune cells (NIH, 2021). This leads to decreased synthesis of pro-inflammatory cytokines (interferon gamma, tumor necrosis factor alpha, interleukin-1, -2, -6, -12 ). Covid-19 is referred to as the cytokine storm with widely distributed inflammation all over the body.  Fluvoxamine can thus be useful as it is anti-inflammatory through reducing cytokine synthesis. 

Reference list:

1.  NIH (National Institutes of Health). 2021. Fluvoxamine COVID-19 treatment guidelines. https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/ Date of access: 27 Oct. 2021

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

Endothelium cells respond to vasorelaxants by releasing soluble endothelium-derived relaxing factor (EDRF). EDRF acts on vascular muscle to cause relaxation. NO is the major bioactive component of EDRF.

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

iNOS are expressed through transcriptional induction (inducible) when exposed to inflammatory mediators and this expression, and thus NO synthesis, is not regulated by calcium. eNOS and nNOS are expressed constituvely (=continuously produced regardless of cells' needs) and NO synthesis is dependent on calcium regulation. Cytosolic calcium forms complexes with calmodulin which then binds and activates eNOS and nNOS.

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

Sepsis is a systemic inflammatory response caused by infection. Endotoxins from the bacterial cell wall along with endogenously generated TNF-alpha and other cytokines, induce synthesis of iNOS in macrophages, neutrophils, T-cells, hepatocytes, smooth muscle cells, endothelial cells and fibroblasts. This widespread synthesis of NO cause aggravated hypotension, septic shock and death. 

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

NO

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

Intracellular glutathione protect against tissue damage caused by scavenging peroxynitrite (peroxynitrite=NO+superoxide; it inhibits protein function and cause tissue damage during inflammation).

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

NO stimulates the synthesis of inflammatory prostaglandins by activating COX-2. The vasodilatory effects of prostaglandins along With NO leads to an increase in vascular permeability and thus lead to perivascular oedema. Excessive NO production may lead to tissue injury (iNOS induction.)

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

- Stroke

- Parkinson's disease

-  Amyothropic lateral sclerosis

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

Hypertension.

An increase in angiotensinogen cause an increase in conversion to angiotensin I through renin. ACE (angiotensin converting enzyme) converts angiotensin I to angiotensin II which activates angiotensin II type 1 receptors. This cause vasoconstriction ( and an increase in peripheral resistance and BP), an increase in aldosterone secretion (increased Na and H2O reabsorption and increased bood volume) and cardiac hypertrophy and remodelling which will aggravate hypertension further. This can 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?

Drugs which blocks ACE will also lead to the inhibition of bradykinin breakdown. Increased bradykinin concentrations cause bradykinin 2 receptor mediated bronchoconstriction (a vagal cough reflex) which cause the negative side-effect of a dry, irritating cough.

Drugs which act specifically on angiotensin receptors will not inhibit bradykinin breakdown and thus will not have this adverse effect because; [bradykinin] will not be increased.

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

ACE inhibitors firstly block the conversion of angiotensin I to angiotensin II. Angiotensin II type I receptors are also blocked. This leads to vasodilation instead of vasoconstriction which leads to a decrease in peripheral resistance and BP. Aldosterone secretion decreases which leads to less salt and water retention and more excretion which lowers cardiac preload, decrease cardiac output and decrease BP. Left ventricular hypertrophy is also reversed.

ACE inhibitors also inhibit bradykinin breakdown. Increased bradykinin concentrations, increase prostaglandin synthesis which increase arterial vasodilation, lowers peripheral resistance and lowers BP. This is all therapeutically useful in hypertension.

• 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?

They act on angiotensin II type 1 receptors. They have no affect on angiotensin II type 2 receptors.

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

Kinins cause vasodilation of arteries and vasoconstriction of veins. Yes, there are many other autacoids that also cause vasodilation; Natriuretic peptides, vasoactive intestinal peptides, substance P, neurokinin A, neurokinin B, Calcitonin gene-related peptide.

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

Bradykinin 2 receptors

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

Natriuretic peptides cause vasodilation which decrease peripheral resistance and decrease BP that can be effective in treating hypertension.

Natriuretic peptides increase glomerular filtration and sodium excretion, decrease renin secretion, decrease sodium reabsorption and decrease the effect of angiotensin and aldosterone. This will relieve the oedema associated with congestive heart failure.

• 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 metabolizes the natriuretic peptides ANP and BNP which lead to a decrease in their concentrations. In reducing ANP and BNP, their positive therapeutic effects in congestive heart failure is also reduced (less vasodilation and rather vasoconstriction,  decreased glomerular filtration and sodium excretion, increased renin secretion, increased sodium reabsorption and increased effect of angiotensin and aldosterone). Thus neprilysin should be blocked so that the therapeutic positive effects of ANP and BNP can dominate.

Neprilysin inhibitor drug: Sacubitril

• Give examples of endothelium-derived vasodilators and vasoconstrictors.

Endothelium derived vasodilators: PGI2, NO (nitric oxide)

Endothelium derived vasoconstrictors: ET1, ET2, ET3, ETA, ETB

Endothelium antagonists that cause vasodilation: Bosentan, macitentan, ambrisentan, sitaxsentan.

Migraine

Pathology

Migraine involves the release of the peptide neurotransmitter, calcitonin gene-related peptide (CGRP), from nerves distributed in cerebral arteries.  This neurotransmitter causes vasodilation and extravasation of blood plasma and plasma proteins into the perivascular space (perivascular oedema).  This causes a mechanical stretching which in turn lead to the activation of pain nerve endings in the dura.

Current treatments

Triptans (e.g. Sumatriptan) are first-line therapy for migraines. They are partial agonists at serotonin 1B/1D receptors and increase intracranial vasoconstriction that prevents the above-mentioned vasodilation that causes pain due to the stretching of sensory nerve endings. These agents may also reduce the release of CGRP and as a result also reduces perivascular oedema in the intracranial circulation.

Ergot alkaloids (e.g. Ergotamine and Ergonovine) have mixed partial agonist effects at serotonin 2 receptors and alpha adrenoceptors. They cause marked smooth muscle contraction but blocks alpha-agonist vasoconstriction. These agents therefore also prevent the above-mentioned vasodilation that leads to pain.

1. what are the general cause of rhinitis & rhinorrhea?

Rhinitis is linked to cold & flu, it is inflammation of the nasal cavity. Mucosal rhinitis is linked to sinusitis. Allergic rhinits is linekd to allergen exposure & IgE. Non-allergic is the physiological reaction.

2. Which drugs can be used for the treatment of rhinorrhea?

• Mast cell stabilizer -> ketotifen
• Alpha1 agonist -> naphozoline
• Moculytic -> Mesna
• Antihistamine -> Loratadine
• Diversdrugs -> Saline
• Antibiotics -> Neomycin
• Corticosteriods -> beclomethasone

3.  How do decongestants differ with respect to the MOA & duration of action ? How are they administered typically?

Vasoconstriction of mucosal blood vessels, which decreases oedema of the nasal mucosa. topical de congestants have fewer side effects than drops, drops can also end up the GIT. the short acting drugs have a 4-6 hour duration, the intermediary acting 8-10 hours & the long- acting have a duration of 12 hours. They are mainly direct acting drugs, mixed action drugs.

4. what is rhinitis medicamentosa ? How is it treated?

May present following chronic treatment with decongestants. Permanent vasoconstriction with poor local blood supply that leads to damage of mucosa membranes of the nose with permanent inflammation & swelling & deregulation of the A-adrenergic receptorson the blood vessels, making them unresponsive to alpha-agonists.

5. How does the first & second gen of antihitamines differ with respectto the mech. according to which rhinits & rhinorrheoa are relived? What are the advantages of the second gen ? Why should they not be used to relieve cold rhinitis?

There is contraversy, however, about the use of antihistamine for the treatment of rhinorrhoea during colds. Bradykinin is the medator of inflmaation here. There is, therefore no rationale for the application of the antihistamine characteristics of the ANTIHISTAMINE. It is however true that the old gen histamines are used for cold rhinorrhoea in view of their antimuscarinic characteristics to dry all watery secretions.

6. When are corticosteroids, anti-allergic drugs, mesna & normal salt solutions valid & how are they administered?

Topical mesna is especiall meaningful to use when the nasal secretion is sticky.

Sodium chromoglycate as a nasal spray for prophylactic treatment of allergic rhinitis.

Normal salt is very safe as nose drops

• Give your own definition of COPD:  it is a combination of lung diseases that prevent airflow resulting in difficulty breathing. Most common conditions that make up COPD are: bronchial asthma, emphysema & chronic bronchitis. These conditions limit pulmonary airflow & gas exchange & can therefore lower life quality by causing sleeping disorders, reducing the ability to perform physical activity. Damage to the lungs from COPD can't be revered.
• Briefly describe the proposed aetiology & pathophysiology of chronic bronchitis & emphysema:

Chronic bronchitis : Is a non-specific obstructive airway disease which the exact aetiology is unclear, characterized by reduced mucus secertion & mucosal clealance, but which is associated with long-term exposure to irritants e.g. cigarette smoke, dust & irritating gases. Chronic bronchitis is due to hypersecretion of mucus, causing chronic cough due to sticky phlegm, an overactive parasympathetic nervous system plays an important role in chronic bronchitis.

Emphysema: Comprises a non-reversible dilation of the respiratory bronchiole & alveoli as a result of structural damage to the walls. The air is, therefore, caught in the respiratory space of the lungs & is exhaled with difficulty, disrupting ventilation of the lungs. It is generally continuous exposure to irritant that damage your lungs & airway.Due to this reason the lungs are being deprived of continuous flow of oxygen therefore causing deeper breathing, leading to SOB.

• Which type of therapy are included in the treatment of a COPD patient? :  Stop smoking, hypoxia (oxygen inhalation), poor lung capacity(regular exercise), airway obstruction ( bronchodilation), surgery( lung transplant) & bacterial infection ( antibiotic against influenza).

• Why is ipratropium more effective in the treatment of chronic bronchitis than in the treatment of bronchial asthma? : Ipratropium is a muscarinic Ach receptor antagonist which prevents the function of the PNS. The function includes: the production of bronchial secretion as well as constriction. With COPD the bronchodilatory effect is usually better than what is achieved with beta2-sympathomimetics. This can be understood, especially in the light of the role  of the PNS in chronic bronchitis, as discussed above.

• In which way do the skeletal muscle effects of theophylline have advantage in the treatment of COPD: Theophylline has the special advantage that it improves diaphragm contractility & reduces diaphragm exhaustion, improves cardiac contractility, lowers pulmonal resistance, improve muscociliary clearance & improves the ventilatory response.

•  What is the role of oxygen therapy in COPD? : Increases the amount of oxygen that flows into your lungs & bloodstream & as a result this improves breathing,

The rationale for using fluvoxamine in the treatment of Covid patients.

Fluvoxamine is a selcetive serotonin reuptake inhibitor (SSRI)  & a potent σ-1 (S1R) receptor agonist The lung tissue damage caused by Covid results in an excessive immune response (also inflammatory) by the patient which further exacerbates a patient's condition.(Lenze et al.,2020:2292).

It has a anti-inflammatory effect & is therefore used to help Covid patients.Fluvoxamine binds to sigma-1 receptor in the immune cells of the body, reducing the production of inflammatory cytokines.

Stimulation of the stigma-1 receptor reduces the synthesis of pro-inflammatory cytokines, thereby reducing systemic inflammation.

References:

Lenze E.J,Mattar C.,Zorumski C.F.,Stevens,A.,Schweiger,J.,Nicol.G.E.,...Reiersen,A.M. 2020. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trail.

https://www.covid10treatmentguidlines.nih.gov/therapies/immunomodulators/fluvoxamine/#:~:text+Anti%2Dlnflammatory%2oEffect%2of%20fluvoxamine,reduced%20production%20of%20inflammatory%20cytokines

Leergedeelte 3.5

1. Verduidelik kortliks wat sistiese fibrose is en hoe dornase-alfa werk om die probleem op te los.

Sistiese fibrose is genetiese metaboliese siekte (Verhoogde DNase 1) wat lei tot verlaagde sekresies in verskeie organe en die ergste simptome kom voor in die lugweë.

RhDNase 1 hidroliseer proteïene in brongiale mukus om vloeibaarheid te verbeter en dus die sekresie daarvan te verbeter.

2. Verduidelik kortliks wat neonatale respiratoriese noodsindroom is, wat die algemene behandelingstrategieë behels en hoe kortisoon en eksogene surfaktante werk om die probleem op te los.

Dit is n siekte wat oppervlakaktiewe stof wat die lugweg bedek en noodsaaklik is vir gaswisseling, word eers kort voor geboorte gevorm, wat kan veeroorsaak dat die longe plat val en tot die dood kan lei in premature babas.

Suurstof om oksiginering te verseker en n ventilator kan gebruik word om positiewe druk te implementer.

Maar wanneer daar verhoogde suurstof oor langtermyn toegedien is lei dit tot retinale skade en blindheid.

Die geneesmiddels vir die behandeling is eksogene surfaktante:  beraktant, poraktant alfa.  Kortikosteroïede (betametasoon) is ook profilakties aan moeder voor kraam toegedien om baba se surfaktant produksie te iniseer 24 uur voor kraam.

3. Wat is die rol van suurstofterapie by neonatale respiratoriese noodsindroom?  Wat behels die gevare van suurstoftoksisiteit?

Die rol van die suurstof is om oksiginering te verseker en n ventilator kan gebruik word om positiewe druk te implementer.Maar wanneer daar verhoogde suurstof (bo nnormale vlakke en wat nie gemonitor word nie) oor langtermyn toegedien is, lei dit tot  retinale skade en blindheid. Daarom moet die suurstof monitering baie deeglik en gereeld gedoen word.

4. Verduidelik kortliks wat neonatale apnee is en hoe die metielxantiene werk om die probleem op te los.  Watter metielxantiene word gebruik?

Dit kom voor wanneer die asemhalingsentrum in brein nog nie volledig ontwikkel het om voordurende asemhaling te stimuleer nie.

Metielxantiene (Kaffeïen, teofillien) word gebruik vir die behandeling omdat dit stimuleer jou sentrale senuwee stelsel wat naamlik jou asemhaling sentrum in die medulla is.

Leergedeelte 3.4

1. Wat is die algemene oorsake van rinitis en rinoree?

Rinitis en Rinoree oorsake:

• Chemiese of geneesmiddel skade
• Koue of hitte
• Infeksie
• Allergiee
• Fisiese skade

2. Watter geneesmiddelgroepe kan by die behandeling van rinoree gebruik word?  Noem voorbeelde by elke groep.

• a1agoniste wat dien as dekogestante = Oxymetasolien
• Antimuskarieniese middels en antihistamiene = Prometasien
• Masselstabiliseerders = Natruimchromoglikaat
• Kortikosteriode= Betametasoon
• Diverse middels= stoom

3. Hoe verskil die dekongestante onderling ten opsigte van werkingsmeganisme en werkingsduur?  Hoe word hulle tipies toegedien?

Die werkings meganisme van al die dekogestante is dieselfe, naamlik om die vasokonstruksie te veroorsaak sodat die mucus se viskositeit kan afneem.

Die werkings duur kan vir jou n idee gee van hoe gereeld die middels geneem moet word.

Kortwerkende middels = (4-6 ure) Fenielefrien

Intermiediere middels = (8-10 ure) Xilometasolien

Langwerkende middels = (12 ure) Oksimetasolien

Hierdie middels moet verkieslik topikaal (drupel, sproei) toegedien word sodat dit n direkte effek kan veroorsaak. As dit oraal toegedien word ontstaan daar meer newe-effekte.

4. Wat is rhinitis medicamentosa?  Hoe word dit behandel?

Dit is n terugslagrinitis wat ontaan agv die oordosering van Topikale middels. Daar word chronies behandel met dekogestante wat vasokontriksie veroorsaak en die premanente behandeling veroorsaak gebreklikke bloedverskaffing en skade aan die bloedvate en tot inflamasie lei. Dit veroorsaak ook dat die bloedvate nie meer n reaksie gaan toon teenoor die a1 reseptore nie en hulle word dan dus onreaktief.

Jy behandel hierdie kondisie met kortermyn kurses van kortikosteroide. Staak eers die geruik van dekogestante end an gaan een neusholte eers gespeen word en herstel sodat jy nog kan asem haal deur die ander neusholte, want sodra die staking van dekogestante plaasvind veroorsaak dit dat die neus weer toe is en voel.

5. Hoe verskil die eerste en tweede generasie antihistamiene ten opsigte van die werkings­meganismes waarvolgens rinitis en rinoree verlig word?  Wat is die voordele van die tweede generasie antihistamiene?  Waarom behoort hulle nie gebruik te word om verkouerinitis te verlig nie?

Eerste generasie antihistamiene kom meer in verkoue preperate voor omdat dit muskarieniese funksies blok. Dit word gebruik vir die behandeling van Verkoue-rinitis.

Tweede generasie antihistamiene blok nie muskariene funksies nie en word dus gebruik vir die vasokontruktiewe effekte.  Slegs gebruik vir die behhandeling van allergiese-rinitis en nie verkoue-rinitis nie. Jou tweede generasie anti- histamiene het ook nie die sedatiewe effek soos jou eerste generasien middels nie.

Anti-histamiene moet nie vir verkoue-rinitis gebruik word nie omdqat dit slym/mucus-indikking kan veroorsaak, asook omdat hitamien nie n rol speel by verkoue nie maar wel Brandikinien (hoes).

6. Wanneer is kortikosteroïede, anti-allergiese middels, mesna en normale soutoplossing bruikbaar en hoe word dit toegedien?

Kortikosteroide = Behandeling van pirvinisme en word topikaal toegedien

Anti-allergiese middels = behandeling van profilakse allergies rhinitis en word topikaal toegedien

Mesna= maak taai neosale mucus vloeibaar en topikaal (neussproei)

Normale soutoplpossing = bevogtig die neus area (neussproei)

Leergedeelte 3.2

1. Gee jou eie definisie van COLS.

Dit staan vir kroniese obstruktiewe lugweg siekte. Dit is n mengsel van brogiale asma, emfiseem en chroniese brongitis wat elkeen tot gevolg lei tot kenmerke en simprome van COPD.

En die hoof effek van COPD is dat dit die pulmonere lugvloei en gaswisselnig beperk.

2. Beskryf kortliks die voorgestelde etiologie en patofisiologie van chroniese brongitis en emfiseem.

Chroniese brongitis:

Die etiologie is onbekend maar dit word wel veroorsaak deur eksterne stimuli (rook, chemikaliee, hitte ens). Dit word gejenmerk duer gereelde bakteriese lugweginfeksie, baie mukusseresie en vertraag mucus opruiming.

Emfiseem:

Dit word veroorsaak deur rook en irritante. Dit veroorsaak struktuele skade aan die brongi en alveholi, wat die lug wat ingeasem word – vasvang end us word dit dan moeilik uitgeasem.

3. Watter tipes terapie word ingesluit om ’n COLS-pasiënt te behandel?

• Staking van rook
• Inenting (vaccinate) teen influenza infeksie en ander bree spektum van bakteriese infeksies.
• Vir hiposie = gee suurstof inhalasies
• Om longkapasiteit te verbeter = gereelde ligte tot matige oefening
• Voorsien brongodilatore om lugwee obstruksie te behandel.
• Om die mucus te Verdun = stoom / rehiralisering

4. Waarom is ipratropium meer effektief by die behandeling van chroniese brongitits as by die behandeling van brongiale asma?

Ipratopium word gebruik vir die brongodilatoriese effekte wat dit voorsien. Dit word slegs vir asma gebruik as jou B2-agoniste teenaangedui is. Die middle se effek op die vagussenuwee speel ook n belangrikke rol.

5. In watter opsig hou die skeletspier-effekte van teofillien voordele in by die behandeling van COLS?

As gevolg van die effekte wat Teofillien het op die diagragma veroorsaak dit kontraksie om dit te versterk. Dit help dus dan veral met COPD pasiente om die ventilasie te verbeter in die gevalle van dispnee en hipoksie.

6. Wat is die rol van suurstofterapie by COLS?

Suurstofterapie se hofdoel tydens COPD is om hiposie (die gevoel dat jy te min suurstof het ) te verbeter en op so manier dus die simptome van n COPD- lyer te verlig.

Leergedeelte 2.5

1. Gee 'n kort en kritiese verduideliking van die rasionaal om fluvoksamien ('n selektiewe serotonienheropname remmer (SSRI) te gebruik in die behandeling van Covid pasiente.  Jou antwoord moet toepaslike verwysings sowel as in-teks verwysings he.

Die gebruik van die middle is om die produksie van inflammatoriese sitokiene te verminder. Dus sal dit n rol speel met COVID tydens die simptome wat ervaar word soos – hoes, met n seer keel, vel uitslag of irritasie op die vel, koors, ens.

Inflamasie is n gswelde rooi reaksie van die liggaam as n verdedigings meganisme teen siektes. Daarom sal Fluvoksamien goed wees met die behandeling van sekere Covid simptome.

SSRI's behandel depressie deur die vlakke van serotonien in die brein te verhoog. Dus in die onsekere tye waarons almal onsself in bevind sal die middle ook kan gebruik word as n anti-depressant. Serotonien is een van die chemiese boodskappers (neurotransmitters) wat seine tussen breinsenuweeselle (neurone) dra. SSRI's blokkeer die herabsorpsie (heropname) van serotonien in neurone.

Leergedeelte 2.4

1. Wat beteken die term “endotelium-afhanklike” vasodilatasie vir jou? Verduidelik.

Dis die belangrikste stimulasie vir NO-vrystelling kom van skuifspanning af. Dit is veroorsaak deur die toename in bloedsnelheid en lei tot vasodilatasie. Die vasodilatasie is eweredig aan die hoeveelheid NO wat deur die endoteel vrygestel word.

2. As ons praat van die NOS-ensieme, wat beteken “konstitueel” en “geïnduseerde” ensieme, en wat is die patologiese en fisiologiese implikasies hiervan?

iNOS- stel voor transkripsie-induksie (induseerbaar) wanneer dit aan inflammatoriese mediators blootgestel isen daar is (geen sintese). Dit word nie deur kalsium gereguleer nie.

eNOS en Nnos- Saam uitgedruk,voortdurend geproduseer ongeag selle se behoeftes en  geen sintese is afhanklik van kalsiumregulering nie. Sitosoliese kalsium vorm komplekse met kalmodulien, bind aan eNOS en nNOS en word geaktiveer.

3. Verduidelik hoe NO tot die noodlottige patologie van septiese skok bydra.

Sepsis is 'n sistemiese inflammatoriese reaksie wat deur infeksie veroorsaak word. Sommige komponente in bakterieë soos endotoksiene, sitokiene en tumornekrose - veroorsaak die vorming van iNOS in die makrofage, T-selle en hepatosiete. Die NO vorming lei tot skok, erge hipertensie en moontlike dood.

4. Watter outakoïede se meganisme van werking berus op effekte op die guanilielsiklase-cGMP-stelsel?

Stikstofoksied

5. NO kan vir die sel toksies wees.  Watter maniere het die liggaam om hierdie nadelige effek van NO teen te werk?

Daar is glutatione teenwoordig en dit is beskermend teenoor weefselskade wat deur piroksinitriet veroorsaak word en tot gevolg ook weeefselskade veroorsaak tydens die inflasie proses. (peroksinitriet inhibeer proteïen funksie)

6. Noem ‘n manier hoe NO pro-inflammatories kan optree.  Gee voorbeelde waar dit voor- of nadele sal hê.

NO stimuleer die sintese van inflammatoriese prostaglandiene deur COX-2-pathway te aktiveer. Prostaglandiene het vasodilatoriese effekte wat dan saam met NO, vaskulêre deurlaatbaarheid verhoog en dit lei tot perivaskulêre edeem.

Oormatige NO-produksie lei tot weefselbesering.

7. In watter moontlike neurologiese en psigiese siektes is NO betrokke?

• Beroerte
• Parkinson's siekte
• Amyothropic lateral sclerosis

Leergedeelte 2.2

1. In watter siektetoestande is angiotensinogeenvlakke verhoog?  Wat is die implikasies hiervan?

Hipertensie en hartversaking

In die siekte toestande is daar ‘n oor aktiwitweit van RAAS wat daartoe lei = dat meer angiotensien II in die liggam en die produksie angiotensinogeen sal verhoog.

Omdat daar nou meer angiotensinogeen teenwoordig is (vir vorming van angiotensien II) sal dit die siekte toetstand vererger agv sy vasokonstruktiewe effekte.

2. Wat is die rede daarvoor dat middels wat die angiotensienstelsel deur werking op angiotensienreseptore rem, minder newe-effekte het as die wat AOE rem?

Omdat dit die negatiewe terugvoer meganisime van ANG II blok wat jou renin vrystelling verhoog. Bradykinin aktiwiteite verhoog (as in oormaat verhoog) erge hoes en angio-edema kan veroorsaak en angiotensien I reseptor blokkers het ‘n laer insedensie van hoes ook.

Die middels is ook gekontra-indikeerd in swangerskap agv fetale nierbeskadiging wat kan ontstaan.

3. Op watter wyse het AOE-remmers ‘n tweevoudige meganisme van werking by die behandeling van hipertensie?

AOE-remmers het ‘n invloed op die angiotensien II sisteem en die bradikinien sisteem = tweevoudige meganisme van werking.

Met die angiotensiensisteem middels veroorsaak dat die AOE geinhibeer word wat lei tot ‘n afname in die vorming van angiotensien II. Hierdie sal dan die bloeddruk verlaag. Die inhibisie veroorsaak ook dat bradikinien nie omgeskakel kan word in onaktiewe metaboliete toe nie (oormaat bradikinien) en dit veroorsaak vasodilatasie en laer bloeddruk.

4. Op watter tipe angiotensienreseptore werk losartan en soortgelyke middels?  Het hulle enige effekte, direk of indirek, op ander angiotensien II-reseptore?

Hulle bind die AT1-reseptor wat in vaskulêre gladdespier en byniere voorkom.

5. Wat is die fisiologiese effekte van kiniene op arterieë en vene?  Speel ander outakoïede ‘n rol in hierdie werking?  Verduidelik.

Hulle verwyd die vene en atriums. Ander outokoïede (stikstofoksied, vasodilatoriese prostaglandiene (PGE2 & PGI2)) speel ook n rol as bemiddelaar in hierdie aksie.

6. Watter reseptor is waarskynlik die mees betrokke in die klinies-belangrike effekte van kiniene?

B2-blokkers

7. Op watter wyse is natriuretiese peptiede moontlik effektief in die behandeling van hipertensie, asook kongestiewe hartversaking?

Natriuretiese peptiede veroorsaak 'n toename in natriumuitskeiding en die vloei van urine. Hierdie lei tot 'n afname in bloedvolume.

Natriuretiese peptiede veroorsaak ook vasodilatasie= afname in arteriële bloeddruk. Al hierdie sal effektief wees in die behandeling van hipertensie en  kongestiewe hartversaking.

8. Wat is neprilisien en wat is die rasionaal om sy aktiwiteit te inhibeer by die behandeling van hartversaking. Kan jy die middel noem wat sodanig gebruik word. Verwys ook na leereenheid 1 waar julle ook met die spesifieke middel te doen gekry het.

Neprilisien metaboliseer ANP & BNP. Deur die aktiwiteit te inhibeer= die effekte van ANP en BNP verleng wat vasodilatasie tot gevolg het. Daar is ook ander meganismes om hartuitwerp en perifere weerstand te verlaag en die meganismes kan lei tot natriurese en diurese en spanning op hartversaking verlig.

Sacubitril is die gewenste geneesmiddel en word in kombinasie met Valsartan gebruik. Valsartan is ‘n ACE-inhibeerder= wat artriële dilatasie veroorsaak (LE 1). Die kombinasie van die twee middels word vir behandeling van hartversaking gegee.

9. Gee voorbeelde van endotelium-afgeleide vasodilatore en vasokonstriktore.

• Vasodilators: Bosentan. (endoteelantagonis)
• Vasokonstriktors: Endotelien 1, 2 + 3.

1. Is a genetic metabolic disease that decreases DNase 1 leading to decreased secretions in various organs. Dornase alpha is a rhDNase inhaler  that hydrolyses the proteins in the bronchial mucosa making the more fluid.

2. Surface active agents( surfactant, which covers airways and is essential for gaseous exchange) is only formed shortly after birth. Corticosteroids (betamethasone) can be given as it starts surfactant production. O2 may be used to ensure oxygenation.

3. O2 is to ensure oxygenation but an increase for a long term periods leads to retinal damage and blindness.

4. It is a respiratory centre in brain not yet fully developed to stimulate continuous breathing seen in new borns and premature babies. Methylxanthines stimulate CNS. Examples include caffeine / theophylline IV for a few weeks

1. Cold, allergies, physical damage, drug or chemical damage.

2. Alpha- antagonist- phenylephrine, corticosteroids- betamethasone, antihistamines- Loratadine, antibiotics- mupirocin, mucolytics- mensa, mast cell stabilizers- ketoifen.

3.  Decongestants cause vasoconstricion of mucosal blood vessels that reduces oedema of nasal mucosa. Local Decongestants have fewer SE eg oxymetazoline (drops). Short acting drugs have a duration of 4 to 6 hours, intermediate acting drugs have a 8 to 10 hour duration and long acting drugs have a 12 hour duration.

4. Rhinitis medicamentosa is the permanent vasoconstriction that has a poor local blood supply leading to the damage of mucosa membranes in the nose and gives permanent swelling and inflammation. Xylomethazoline may only be used for a few days cause rhinitis medicamentosa may develop.

5. 1st gen, used for rhinorrhea, 2nd gen used for allergic rhinitis. 2nd gen doesn't block muscarinic receptors and doesn't cause sedation like the first gen.

6. Corticosteroids- used for allergic rhinitis, administration is topical, anti-allergic drugs- prophylactic treatment of allergic rhinitis given as a nasal spray. Mensa- makes mucus a liquid given as a nasal spray. Normal salt solution- nasal lavage.

1.  COPD has a different degree of combinations such as bronchial asthma, chronic bronchitis and emphysema. This limits the limit air flow as well as gaseous exchange.

2. Chronic bronchitis is a non-specific COPD that is characterised by increased mucus secretion, decreased mucociliary clearance, regular bacterial respiratory infections, structural changes in bronchial walls and a chronic cough due to thick mucus.

Emphysema is often developed from smoking and irritants. Irreversible widening of respiratory bronchioles and alveoli. Air is trapped in lungs which equals difficult expiration. A decreased capillary blood vessels. Impededs gaseous exchange.

3. Treatment includes stop smoking. You may develop bacterial infection such as influenza immunization and broad spectrum antibiotics which can be treated with tetracycline, amoxicillin, ampicillin erythromycin. In the airflow obstruction give bronchodialtors. In mucus secretion dilate mucus with rehydration and steam. In hypoxia give oxygen inhalation. In poor lung capacity light moderate exercise will help.

4. Beta-sympathomimetics can improve mucociliary clearance. Ipratropium inhalation is currently the first line of drug treatment for COPD, the bronchodiatory effect is better achieved with beta-sympathomimetics.

5. Theophylline improves the contraction function of the diaphragm, further improves cardiac contractions and improves ventilatory capacity.

6.  The combination of beta-sympathomimetic, ipratropium and Theophylline may help bring relief however corticosteroids may be given if the above medications don't work. Corticosteroids are mostly ineffective so if needed oxygen therapy should be given.

Fluvoxamine has an anti-inflammatory effect which binds to sigma-1 receptors, reducing the building of inflammatory cytokines, this therefore can help patients that have covid. 

https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/#:~:text=Anti%2DInflammatory%20Effect%20of%20Fluvoxamine,reduced%20production%20of%20inflammatory%20cytokines. 

Since covid can lead to serious illnesses, Fluvoxamine can prevent deterioration of the immune cells seen due to fluvoxamine regulating cytokine production.

1. It increases the intracellular Ca levels causing the synthesis of NO going to smooth muscle and causing vasorelaxation.

2.Constitutive-enzymes being synthesized at the constant rate, in constant amounts being regulated by Ca. Inducible- enzymes present in minute concentrations, which when a substrate is added it incraeses the enzyme. However this enzyme is not regulated by Ca causing and accumulation of iNOS producing an increase in NO.

3. Endotoxin components produce TNF which iduces iNOS synthesis in T cells, smooth muscles and macrophages. This inturn can cause shock and hypotension.

4. NO gas

5.NO reacts with heme which converts NO to nitrate, NO reacts with hemoglobin which can transport NO all round the vasculature.

6. NO acts as a pro-inflammatory due to it being an immune regulator. Disadvantage include extended production leading to worsened tissue injury. 

7. Stroke and parkinsons disease

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

This disease is Hypertension ,an increase in the angiotensinogen through renin causes it to convert to angiotensin II. This causes vasoconstriction and increases the secretion of aldosterone.

Why do drugs which inhibit the angiotensinogen system by acting on angiotensin receptors have fewer side effects than those that inhibit ACE?

Drugs which block ACE will also reduce the amount of bradykinin 2.However, drugs which act on angiotensin receptors may not inhibit the breakdown of bradykinin.

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

ACE inhibitors block the conversion of angiotensin 1 to angiotension 2. This prevents the breakdown of natriuretic peptides which decreases angiotension 2 synthesis leading to vasodilation, decreasing blood pressure. Aldosterone secretion is also decreased which would normally reabsorb NaCl if the BP is low in order to increase it . Since aldosterone is decreased the blood pressure will be decreased leading to the treatment of hypertension.

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?

Angiotensin 2 type 1 receptors which have no effect on type 2 receptors.

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

Kinins are potent vasodilators causing dilation of arteries and veins, and many autacoids play a role such as Natriuretic peptides, vasoactive peptides, substance P, neurokinin A and B and CGRP.

Which receptor is probably the most involved in the important clinical effects of kinins? Bradykinin 2 receptors.

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

Natriuretic peptides cause vasodilation which can cause a decrease in blood pressure, effective in the treatment of hyperstion. It increases GF and Na secretion, decrease renin and aldosterone secretion, which relieves fluid build up helping with congestive heart failure.

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.

Neprylisin metabolises natriuretic peptides ANP and BNP. In a reduction of ANP and BNP their effect on CHF patients will be reduced, leading to vasoconstriction with an increase in GF and Na excretion as well as renin secretion being increased causing an increase in blood pressure. Sacubitril which is a Neprilysin inhibitor.

Give examples of endothelium-derived vasodilators and vasoconstrictors.

Endothelium-derived vasodilators: NO and PGI2,  Endothelium-derived vasoconstrictors: ET1,2,3 and ETA,B

Migraine Pathology:

The trigeminal nerve is a vascular nerve that supplies neurotansmitters, such as CGRP, to the intracranial and extracranial arteries.

This neurotransmitter causes the blood plasma and plasma proteins to enter the perivascular space, which then activates the mechanical stretching of the dura.

These neurotransmitters can produce vasodilation, which can cause perivascular oedema. It can also cause mechanical stretching and activation of pain nerve endings.

Treatment for migraine: 5-HT 1D/B receptor agonists such as sumatriptan. 

Ergot alkaloids that are vasoselective such as ergotamine which causes marked smooth muscle contraction.

Furthermore Beta blockers can also be used for the treatment of migraine as well as NSAIDS.

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.

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

It is a genetic defect which leads to reduced secretions in various organs. Dornase alpha hydrolyses extra-cellular DNA from the neutrophils in bronchial mucus and increases 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 is also known as hyaline membrane disease and occurs in premature babies. It is basically when the surface-active material that covers the respiratory unit of the airways is not form, when babies are born prematurely.

Intensive monitoring of respiratory and circulatory status is essential . Exogenous surfactants are administered exogenously at room temperature( by means of  a catheter into the lungs

A short course of corticosteroids is effective to boost endogenous surfactant production and is a cheaper alternative.

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

Oxygen therapy is administered with air at room temperature to ensure oxygenation. a continuous positive pressure improves ventilation and keeps the alveoli open in order to prevent collapse. It is administered in order to prevent collapse.

Dangers. oxygen toxicity causes reduced drug exchange, hypoxia and death in extreme cases. It can also cause retinal damage and blindness.

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

 Neonatal apnoea occurs when the respiratory centre in the medulla has not yet fully developed in premature babies to stimulate continuous breathing.

Methylxanthines, caffeine and theophylline stimulate the CNS and IV administration of these drugs help solve the problem.

• What are the general causes of rhinitis and rhinorrhoea?

 Rhinitis and rhinorrhoea are caused by cold and flu, sinitus, allergen exposure (IgE mediated inflammation and physiological response due to stimuli (heat, smoke and cold weather).

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

Antihistamine e.g. diphenhydramine

corticosteroids e.g. mometasone

mucolytics e.g. mesna

alpha-1 agonists e.g. phenylephrine 

Anti-allergy drugs (sodium cromoglycate)

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

Decongestants MOA ( causes vasoconstriction of the mucosal blood vessels and decreases oedema of nasal mucosa)

short-acting drugs (4-6 hours) ephedrine, phenylephrine

intermediate acting drugs (8-10 hours), xylometazoline

long acting drugs (12 hours) oxymetazoline

They are administered  in the topical dosage form (nasal spray, drops and jellies) and inhalation of volatile compounds.

• What is rhinitis medicamentosa?  How is it treated?

Also known as rebound congestion or Privinism results from an overdose of local preparations. basically presents after chronic treatment with decongestants, where the permanent vasoconstriction with poor local blood supply leads to damage of the mucous membranes of the nose with inflammation and swelling.

Treatments: stop using the decongestants. gradually decrease your use of the medicine and for mild congestion use a saline nasal spray.

• 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?

1st generation antihistamines are multipotent competing antagonist and blocks muscarinic receptors. Antimuscarinic drugs will reduce the secretions of both the upper and lower airways and are included in preparations for colds and clear up rhinnorhoea. 1st generation anti-histamines can cause sedation.

2nd generation anti-histamine do not block muscarinic receptors and are used in the long term or short term treatment of allergic rhinitis. these drugs do not help with the clear up of cold rhinitis, because histamine plays no part in cold rhinitis ( only bradykinin)

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

 corticosterioids- administered for allergic rhinitis, nasal sprays administered through nasal cavity.

anti-allergy drugs- allergic rhinitis and administered as a nasal spray

mesna- when nasal spray secretions is sticky and administered as a nasal spray.

normal salt solution- allergic rhinitis, mild congestion (nose drops)

• Give your own definition of COPD. 

Chronic obstructive pulmonary disease is basically a group of diseases (emphysema, Bronchial asthma, and chronic bronchitis) which causes blockage of airflow and breathing problems.

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

Chronic bronchitis- aetiology- long term exposure to irritants, smoking.

  -pathophysiology- obstructive airway disease due to an increase secretion of mucus, decrease in mucus clearance and frequent bacterial respiratory infections.

Emphysema- aetiology- smoking and irritant

-pathophysiology- air sacks (alveoli) is damaged and the inner walls of the alveoli weakens and rupture creating larger than normal air spaces and this reduces the surface area of the lungs and amount of oxygen reaching the lungs.

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

Treatment includes anticholinergics, B2-agonists and slow-release theophylline, corticosteroids and oxygen therapy.

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

It is first line bronchodilator in the treatment of chronic bronchitis and it is used in treating the symptoms of chronic bronchitis and not in the treatment of bronchial asthma

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

It improves the contraction function of the diaphragm and thus increases ventilatory capacity.

• What is the role of oxygen therapy in COPD?

If a patient presents with low oxygen levels in their blood oxygen therapy can be used to restore the oxygen levels in the blood and prevention of hypoxia.

• Give a short and critical explanation of the rationale of using fluvoxamine (a selective serotonin reuptake inhibitor (SSRI) in the treatment of Covid patients. Your answer must be properly and appropriately referenced (in-text references as well).

According to Hashimoto (2021) Sars Cov-2 binds itself to the ACE2 receptor on the cells and this ultimately results in the activation of the acid sphingomyelinase which is responsible for the conversion of  sphingomyelin to ceramide. ASM/Ceramide system can facilitate viral entry. Fluvoxamine, which is an antidepressant inhibits ASM and formation of ceramide-enriched membrane domains and this results in decreased viral entry. The sigma-1-receptor agonist fluvoxamine may alternate ER stress due to SARS-COV-2 replication in cells, thus resulting in blockade against inflammatory events. thus early administration of fluvoxamine may block/delay clinical deterioration in individuals with SARS-COV-2 infections.

Resource

Hashimoto, Y., Suzuki, T., Hashimoto, K. 2021. Old drug Fluvoxamine, new hope for covid-19. Eur Arch Psychiatry an Neurosci (2021). https://doi.org/10.1007/500406-021-01326-z

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

An increase in blood flow stimulates endothelium-dependent vasodilation by increasing shear stress on the endothelium, both in conduit and resistance vessels.

• 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: they are always produced whether or not a suitable substrate is present and this affects the process by which the synthesis occur and it is always present in the organism in constant amounts .

inducible enzymes: only expressed under conditions in which it is clearly of adaptive value ( used for breaking down of things in the cell).

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

The physiological production of NO is important for blood pressure regulation and blood flow distribution. A hyperproduction of NO by the inducible form of NO synthase (iNOS) may contribute to the hypotension, cardio depression and vascular hyporeactivity in septic shock. 

• 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?

Nitric oxide is a potent and rapid inducer of methemoglobinemia. Exposure to Nitric Oxide may result in changes of the pulmonary system.

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

NO is considered as a pro-inflammatory mediator. It induces inflammation due to over production in abnormal circumstances. Advantages: NO inhibitors represents an important therapeutic advance in the management of inflammatory diseases. They are proved to be used for the treatment of of NO-induced inflammation. Disadvantages: due to impaired production of vasoconstriction, inflammation and tissue damage.

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

Autism spectrum disorder, schizoprenia, (may play a role in the development of it). Bipolar disease, migraine, epilepsy, addiction.

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

  Decrease in blood pressure (hypotension). It increases blood pressure by constricting the blood vessels, it triggers thirst and the desire for salt. Increased levels of angiotensin can result in excess fluid being retained by the body.

• Why do drugs which inhibit the angiotensinogen system by acting on angiotensin receptors have fewer side effects than those that inhibit ACE?

The ACE inhibitors lowers blood pressure by preventing the production of Angiotensin II, while Angiotensin receptor blockers reduce the action of angiotensin II  to prevent blood vessel constriction.

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

It helps to relax the veins and arteries to lower blood pressure and it prevents an enzyme in the body from producing angiotensin II which is a substance that narrows blood vessels.

• 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?

They bind the AT1 receptor found in vascular smooth muscle and adrenal gland.

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

Kinins induce vasodilation, Increasing blood flow  throughout the body and a brief fall in blood pressure. 

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

Bradykinin displays the highest affinity for B2 ( bradykinin 2 Receptors)

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

Natriuretic Peptides may be administered as recombinant ANP, recombinant BNP or ularitide. They produce vasodilation and natriuresis and have been investigated for the treatment of congestive heart failure. Natriuretic Peptides causes vasodilation and this helps to dilate the arteries (increase in blood flow) and this leads to a fall in blood pressure and this is effective in the treatment of hypertension. 

• 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 is a zinc-dependent metalloprotease and it blocks Ang II receptors. It is used to treat high blood pressure and heart failure. By blocking its action it prevents the breakdown of natriuretic peptides. Drugs are omapatrilat, sampatrilat and fasidotrilat. 

• Give examples of endothelium-derived vasodilators and vasoconstrictors.

endothelium-derived vasodilator/ endothelium-derived relaxing factor- Nitric oxide: plays a role in endothelial functions.

endothelium-derived vasoconstrictors/ endothelium-derived contracting factors- Endothelin-1 and Cox-derived thromboxane.

• Verduidelik kortliks wat sistiese fibrose is en hoe dornase-alfa werk om die probleem op te los.

Sistiese fibrose is ń genetiese effek wat sekresies van organe verminder. Dornase-alfa hidroliseer DNA van die neutrofiele in mukus, met die oog om vloeibaarheid van die mukus te verbeter.

• Verduidelik kortliks wat neonatale respiratoriese noodsindroom is, wat die algemene behandelingstrategieë behels en hoe kortisoon en eksogene surfaktante werk om die probleem op te los.

Wanneer die oppervlakvloeistof van die longe wat gaswisseling laat plaasvind eers laat in die swangerskap ontwikkel. Die behandeling behels suurstofterapie, positiewe druk deur ń ventilator en eksogene surfaktante. Surfaktante verlaag spanning met die oppervlak en voorkom dat die alveoli platval.

• Wat is die rol van suurstofterapie by neonatale respiratoriese noodsindroom?  Wat behels die gevare van suurstoftoksisiteit?

Suurstof verseker oksigenering. Suurstoftoksisiteit kan lei tot retinale skade of selfs blindheid.

• Verduidelik kortliks wat neonatale apnee is en hoe die metielxantiene werk om die probleem op te los.  Watter metielxantiene word gebruik?

Wanneer die asemhalingsentrum van die medulla nog nie ontwikkel is nie. Die xantiene stimuleer die sentraal senuweestelsel. Kaffeïen en Teofillien word gebruik.

• Wat is die algemene oorsake van rinitis en rinoree?

Rinitis en rinoree word veroorsaak deur allergieë, verkoue, chemiese- of geneesmiddelskade, koue lug of fisiese skade.

• Watter geneesmiddelgroepe kan by die behandeling van rinoree gebruik word?  Noem voorbeelde by elke groep.

Alpha-agoniste: beta-fenieletielamienderivate wat direkwerkend is bv. Fenielefrien.
Beta-fenielefrienamienderivate wat gemengde werking het bv. Efedrien, Fenielpropanolamien, Propielheksidrien, Pseudoefedrien.
Imidasolienderivate wat gemengde werking het bv. Nafasolien, Tetrahidrosolien, Oksimetasolien en Silometasolien.

• Hoe verskil die dekongestante onderling ten opsigte van werkingsmeganisme en werkingsduur?  Hoe word hulle tipies toegedien?

Fenielefrien, Efedrien, Propielheksidrien, Nafasolien en Tetrahidrosolien is kortwerkend.
Silometasolien is intermediêrwerkend.
Oksimetasolien is langwerkend. Topikale doseervorme en inhalasie word algemeen gebruik.

• Wat is rhinitis medicamentosa?  Hoe word dit behandel?

Word ook privinisme genoem. ń Toestand wat ontstaan na chroniese behandeling met dekongestante. Skade word gerig aan die neusslymvliese met permanente inflammasie en swelling. Daar is ook afregulering van die alpha-adrenergiese reseptore op die bloedvate, sodat dit onresponsief raak teenoor die alpha-agoniste.

• Hoe verskil die eerste en tweede generasie antihistamiene ten opsigte van die werkings­meganismes waarvolgens rinitis en rinoree verlig word?  Wat is die voordele van die tweede generasie antihistamiene?  Waarom behoort hulle nie gebruik te word om verkouerinitis te verlig nie?

Eerste generasie blokkeer muskariene reseptore. Dit verminder sekresies van hoër en laer lugwee.
Tweede generasie blokkeer nie muskariene reseptore nie, is bruikbaar by lang- en korttermynbehandeling van allergiese rinitis. Slymindikking meer by eerste generasie.
Histamien speel nie ń rol by verkouerinitis nie, maar wel Bradikinien.

• Wanneer is kortikosteroïede, anti-allergiese middels, mesna en normale soutoplossing bruikbaar en hoe word dit toegedien?

Kortikosteroïede word gebruik in allergiese rinitis en kan topikaal of sistemies toegedien word. Anti-allergiese middels is baie effektief in profilaktiese behandeling van allergiese rinitis en word as neussproei toegedien. Mesna is sinvol in die gebruik teen taai nasale mukus en word as neussproei toegedien. Soutoplossing is baie veilig en effektief en word as neussproei toegedien in verkoue, droë weer, allergieë, neusbloeding, oorgebruik van dekongestante en ander irritasies.

• Gee jou eie definisie van COLS.

Behels obstruksie in die lugweë weens ń sekere toestand of siekte. Dit sluit in chroniese brongitis, brongiale en emfiseem.

• Beskryf kortliks die voorgestelde etiologie en patofisiologie van chroniese brongitis en emfiseem.

Chroniese brongitis is ń langtermyn gevolg van irritante van die lugweë bv. Sigaretrook, stof en irriterende gasse. Simptome sluit in baie mukus afskeiding, min mukosilêre opruiming, gereelde bakteriële lugweginfeksies en veranderinge in wande. Weens taai slym ontwikkel hoes.
Emfiseem is skade aan die wande wat dan ń onomkeerbare verwyding van respiratoriese brongioli en alveoli het. Gasuitruiling word ook belemmer deur vermindering van kappilêre bloedvatvoorsiening.

• Watter tipes terapie word ingesluit om ’n COLS-pasiënt te behandel?

Anticholinergiese middels, B2-simpatomimetika, teoxantiene, kortikosteroïede en antibiotika.

• Waarom is ipratropium meer effektief by die behandeling van chroniese brongitis as by die behandeling van brongiale asma?

Tiotropium het ń langewerkende gebruik in KOLS en het ń invloed op die vagussenuwee. Die vagus senuwee veroorsaak ń baie aktiewe parasimpatiese senuweestelsel. Ipratropium is ń parasimpatolitiese middel en sal goed werk vir brongitis.

• In watter opsig hou die skeletspier-effekte van teofillien voordele in by die behandeling van COLS?

Kontraksie van die diafragma verbeter ventilasie met asemhaling, verminder hipoksie en dispnee in KOLS pasiënte.

• Wat is die rol van suurstofterapie by COLS?

KOLS veroorsaak hipoksie en die suurstofterapie help met die behandeling van die hipoksie.

It was noted that the production of inflammatory cytokines was decreased after a study done with sepsis on mouse. The reason for this is because of fluvoxamine that binds in immune cells, specifically to the sigma-1 receptor. A decrease of the expression of inflammatory genes was also noted after an in vitro study took place. It was found that fluvoxamine caused this decrease. To determine if the anti-inflammatory effects of fluvoxamine detected do occur in humans and are applicable in COVID-19 there needs to be more investigation and studies (National Institutes of Health, 2021).

National Institutes of Health. 2021. Fluvoxamine: Anti-Inflammatory Effects of Fluvoxamine and Rationale for Use in COVID-19. https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/  Date of access: 27 Oct. 2021

• Wat beteken die term “endotelium-afhanklike” vasodilatasie vir jou? Verduidelik.

Dis ń mengsel van vasodilatoriese produkte en stikstofoksied wat in endoteel gesintetiseer word en daarvan vrygestel word.

• As ons praat van die NOS-ensieme, wat beteken “konstitueel” en “geïnduseerde” ensieme, en wat is die patologiese en fisiologiese implikasies hiervan?

Beide is twee vorme van stikstof oksied sintase. Die eers genoemde gevind in epiteel- en neuronale selle asook endoteel selle en die tweede gevind in makrofae en gladderspierselle.
Veroorsaak verander van arginien na sitrullien en stikstofoksied.

• Verduidelik hoe NO tot die noodlottige patologie van septiese skok bydra.

Sepsis word veroorsaak deur ń infeksie wat lei tot ń inflammatoriese respons. Die sintese van iNOS in makrofae, neutrofiele, T-selle, hepatosiete, gladdespierselle, endoteel selle en fibroblaste for geïnduseer. Die resultate van die wydverspreide stikstofoksied gee verergerde hipotensie, skok en in sommige gevalle dood.

• Watter outakoïede se meganisme van werking berus op effekte op die guanilielsiklase-cGMP-stelsel?

Stikstofoksied.

• NO kan vir die sel toksies wees.  Watter maniere het die liggaam om hierdie nadelige effek van NO teen te werk?

Superoksied kan stikstofoksied omskakel van ń voodelige seiningsmolekule na ń reaktiewe reaktiwe nitrerende spesies. Versagting van peroksienitriet gemediëerde protein modifikasie vind plaas deur middel van intrasellulêre vlakke van glutation. Hierdie het ń beskermende effek teen weefselskade deur opruimings peroksienitriet.

• Noem ‘n manier hoe NO pro-inflammatories kan optree.  Gee voorbeelde waar dit voor- of nadele sal hê.

Dit tree pro-inflammatories op deur werwing van leukosiete en vrystelling van inflammatoriese bemiddelaars.
ń Voordeel van die gebruik van NO is dat dit ń belangrike rol speel in die beskerming van die liggaam deur immuunsel funksie.
ń Nadeel van die gebruik van NO is dat wanneer die stikstofoksied vir te lang periodes gebruik word, kan dit tot weefselskade lei.


• In watter moontlike neurologiese en psigiese siektes is NO betrokke?

Beroerte, amyotopiese laterale sklerose en Parkinson se siekte.
Alzheimer se siekte en skisofrenie.

• In watter siektetoestande is angiotensinogeenvlakke verhoog?  Wat is die implikasies hiervan?

Hipertensie; wanneer angiotensinogeenvlakke verhoog sal renien angiotensien verhoog. Die omskakeling van angiotensien 1 na angiotensien 2 vind plaas deur AOE inhibeerders. Dit aktiveer angiotensien 2 tipe 1 reseptors. Vasokonstriksie sal plaasvind asook aldosteroon afskeiding, kardiale hipetrofie en hermodellering. Die implikasie is dat hipertrofie sal vererger.

• Wat is die rede daarvoor dat middels wat die angiotensienstelsel deur werking op angiotensienreseptore rem, minder newe-effekte het as die wat AOE rem?

Angiotensien reseptor blokkers (ARB's) se werking is soorgelyk aan AOE inhibeerders, maar met minder gevalle van hoes. Die ARB's het ń verlaging getoon in die gevalle diabetes wat ontwikkel in pasiënte met glukose toleransie. Wanneer AOE inhibeerders nie goed ervaar word nie kan hierdie antagoniste as alternatief beskou word vir effektiewe behandeling van hart versaking.

• Op watter wyse het AOE-remmers ‘n tweevoudige meganisme van werking by die behandeling van hipertensie?

AOE inhibeerders verhoog die plasma renien aktiwiteit deurdat dit die negatiewe terugvoer aksie van angiotensien 2 op renien onderbreek.
Sonder dat daar ń verhoging in hartklop en natriurese is kan bloeddruk verlaag word en op die manier werk dit tweevoudig.

• Op watter tipe angiotensienreseptore werk losartan en soortgelyke middels?  Het hulle enige effekte, direk of indirek, op ander angiotensien II-reseptore?

Middels soos Losartan werk op AT1 reseptore. Langdurige werking kan AT2 reseptore stimuleer.

• Wat is die fisiologiese effekte van kiniene op arterieë en vene?  Speel ander outakoïede ‘n rol in hierdie werking?  Verduidelik.

Die effek van kiniene op arteries is vasodilatasie en die teenoorgestelde nl. vasokonstriksie op venas. B1 en B2 is hierby betrokke, maar meestal B2.

• Op watter wyse is natriuretiese peptiede moontlik effektief in die behandeling van hipertensie, asook kongestiewe hartversaking?

Vasodilatasie word veroorsaak, dit verlaag perifere weerstand en bloeddruk wat effektief kan wees in behandeling van hipertensie. En by behandeling van hartversaking is dit vanweë edeem wat verlig word wat saam die hartversaking gaan dat dit effektief is in die behandeling van hartversaking.


• Wat is neprilisien en wat is die rasionaal om sy aktiwiteit te inhibeer by die behandeling van hartversaking. Kan jy die middel noem wat sodanig gebruik word. Verwys ook na leereenheid 1 waar julle ook met die spesifieke middel te doen gekry het.

Neprilisien is ń alomteenwoordige neutrale endopeptidase, deur dit te inhibeer verhoog sirkulasievlakke van natriuretiese peptiede asook natriurese en diurese.

• Gee voorbeelde van endotelium-afgeleide vasodilatore en vasokonstriktore.

Bosentan, masietentan, sitaksen, ambrisentan endoteel derivaat vasodilatore

Patologie:

Migraine vereis verspreiding na kraniaal arteries vind vanaf die 5de kraniaal senuwee plaas. Peptied neuro-oordagstowwe word vrygestel deur die 5de kraniaal senuwees Veral die indrukwekkende vasodilator, kalsitonien geen verwante peptied. Dus vind vasodilatasie plaas.
In mense en diere is gevind dat die opstoot van plasma en plasma proteïne in die perivaskulêre spasie ook algemeen voorkom. Die pyn van migraine kom van die meganiese rek/strek van die perivaskulêre edeem.

Behandeling:

Ergot derivate is potente vasokonstriktore. Dit kan in die begin stadium van ń migraine toegedien word. Hierdie werking is langdurend en daarom is dit noodsaaklik om te hou by die daaglikse of weeklikse dosis. Indien nie daarby gehou word nie, kan ongewensde effekte verwag word.

In meeste pasiënte word Sumatriptan gebruik as behandeling van erge akute migraines. In sommige gevalle help Aspirien en Ibuprofeen om pyn te beheer. Triptane is selektiewe agoniste (slegs gedeeltelik) vir die reseptore Serotonien 1B en Serotonien 1D. Die Triptane serotonien 1 agoniste word as meer effektiewe behandeling beskou teenoor ouer middels. Hierdie middels se effekte mag insluit dat kalsitonien geen verwante peptiede se vrystelling verlaag word en ook perivaskulêre edeem in die serebrale sirkulasie.

1. Kortikosteroïede, skildklierhormone, esterogeen, angiotensien II, in swanger vroue en vrouens wat orale voorbehoedmiddles gebruik wat esterogeen bevat, verhoog die produksie van angiotensienogeen. Die implikasies van verhoogde angitensienogeen vlakke word met noodsaaklike hipertensie geassosieer.

2. Die RAAS- stelsel word meer spesifiek geteiken deur dwelms wat die angiotensienogeen stelsel inhibeer, as die angiotensien reseptore wat vroeër op die RAAS-stelsel inwerk. Die angiotensien reseptorblokkers verlaag die bloeddruk, deur bloedvate te dilateer sodat die hart makliker bloed pomp. Angiotensien veroorsaak dat bloedvate kontrakteer en dit veroorsaak dat die hart harder moet werk om effektief te pomp.

3. ACE-I: Inhibeer die omskakeling van angiotensien I na angiotensien II, dus kan dit gebruik word om hipertensie te behandel. Dit verminder dan ook die natrium- en waterherabsorpsie. Dus sal die bloeddruk afneem en die hart werk harder om effektief te pomp.

AOE-I: Bradikinien katabolisme word geïnhibeer en veroorsaak vasodilatasie, wat ook die perifêre weerstand verminder. Dus sal die bloeddruk afneem en die hart werk herder om effektief te pomp.

4. Losartan en soortgelyke middels tree selektief op, op AT-1 reseptore. AT-1 reseptore is 'n subtipe angiotensien reseptor. Indien die middels oor 'n langtydperk gebruik word, word die renien vrylating geïnhibeer en dit verhoog die sirkulerende angiotensien II vlakke. 'n Verhoogde stimulasie van AT-2 reseptore is ook moontlik en dus het hierdie middels 'n indirekte effek op AT-2 resptore. Losartan het 'n groter affiniteit vir AT-1 resptore, as vir AT-2 reseptore. Die middels veroorsaak vasokonstriksie en aldosteroonafskeiding. 

5. Kiniene is sterk vasodilatore, veroorsaak edeem, sametrekking van die gladde spiere, pyn en hiperalgesie deur die C-vesels te stimuleer. Die vrystelling van NO, PGE2, PGI1, Kalsiummobilisasie, Chloriedvervoer, die aktivering van Fosfolipase C en Fosfolipase A2. Die dien as tweedeboodskappers in die seintransduksiestelsel. 

6. Bradikinien 2 reseptore is die meeste betrokke by die belangrike kliniese effekte van kiniene.

7. Natriuretiese peptiede (ANP en BNP), speel 'n groot rol in kardiovaskulêre homeostase. Hul eienskappe sluit vasodilatasie, diurese, natiurese en die remming van hartvervorming in. Dus kan natiuretiese peptiede moontlik effektief wees in die behandeling van hipertensie en kongestiewe hartversaking. 

8. Neprilisien is 'n ensiem, dit word gekodeer deur die MME- geen en metaboliseer ANP en BNP. . Neprilisien blokkers is 'n nuwe klas medikasie en word gebruik in die behandeling van hipertensie en hartversaking. Die middels blokkeer Neprilisien en voorkom dat natiuretiese peptiede nie afgebreek word nie. Middels byvoorbeeld, Valsartan en Sacubutril.

9. Vasodilatore: Vasomera, VIP, Stof P, CGRP

Vasokonstriktors: NPY 

Patologie van migraine:

'n Migraine is 'n baie erge hoofpyn wat somtyds gepaard gaan met naarheid, braking en sensitiwiteit teen lig en klank. Die oorsaak is nie altyd duidelik nie, maar hormonale veranderinge, sekere eet- of drinkgied, stres en oefening kan daartoe bydra. Dit kan tot paar dae aanhou. 

Middels waarmee migraine behandel kan word, sluit in:

Beta- antagoniste:

Propanolol, Nadolol, Timolol, Amitriptyline- Verminder die gereeldheid en die intensiteit wat migraines voorkom. Die meganisme van hoe dit help met migraines is nie bekend nie. Dit help nie vir pasiënte met akute migraine nie, maar is wel net profilakse van migraine.

Ergotalkaloïede:

Die middels is spesifiek vir migraines. Die vasokonstriksie wat deur Ergotamien geïnduseer word, is langwerkend wanneer dit herhalend geneem word. Nasale dihidroergotamien kan ook effektief wees, vir die behandeling by migraines. 

Serotonien:

Sumatriptaan, Naratriptaan- Dis gedeeltelike 5-HT 1D/B agoniste. Dit verhoog die intrakraniale vasokonstriksie, om die vasodilatasie teen te werk. Die vasodilatasie veroorsaak die pyn in 'n migraine. Dit sluit medikasie bv. Imigran in.

Give a short and critical explanation of the rationale of using fluvoxamine (a selective serotonin reuptake inhibitor (SSRI) in the treatment of Covid patients. Your answer must be properly and appropriately referenced (in-text references as well).

According to National Institutes of Health (NIH, 2021) fluvoxamine is a selective serotonin reuptake inhibitor (SSRI). It is approved by the  Food and Drug Administration (FDA) for the treatment of obsessive-compulsive disorder. It is also used in depression and other conditions.

The studies that have been done, show that fluvoxamine was found to bind to the sigma-1 receptor in immune cells, resulting in reduced production of inflammatory cytokines. It also reduces the expression of inflammatory genes in an invitro study of human endothelial cells and macrophages.

In the Medical letter (Medical letter, 2021:63) it is written that sigma-1 agonism has been shown to inhibit SARS-CoV-2 replication and to modulate the inflammatory response to sepsis. It could theoretically prevent development of life-threatening cytokine storm and acute respiratory distress syndrome in COVID-19.

 According to the article from K. Hashimoto (NIH ,2021) the sigma-1 receptor in the endoplasmic reticulum plays an important role in SARS-CoV-2 replication in cells. Knockout and knockdown of SIGMAR1 (sigma-1 receptor, encoded by SIGMAR1) caused robust reductions in SARS-CoV-2 replication, which indicates that the sigma-1 receptor is a key therapeutic target for SARS-CoV-2 replication.

Reference list:

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

NIH (National institute of health). 2021. https://pubmed.ncbi.nlm.nih.gov/33403480/ Date of access: 13 Oct. 2021

Medical letter. 2021.https://secure.medicalletter.org/sites/default/files/freedocs/w1623d.pdf Date op access: 13 Oct. 2021