• Gee jou eie definisie van COLS.

'n Kroniese obstruktiewe lugwegsiekte: 'n siekte wat lank aanhou (chronies) wat te doen het met 'n obstruksie in die lugweg wat asemhaling moeilik maak. Gewoonlik 'n kombinasie van brongiale asma, chroniese brongitis en emfiseem.

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

Chroniese brongitis 

Etiologie: Onseker; word wel geassosieer met langtermyn blootstelling aan irritante soos bv sigarette, stof en sekere gasse.

Patofisiologie: Nonspesifieke obstruktiewe lugwegsiekte

Emfiseem 

Etiologie: Ontwikkel agv rook en irritante

Patofisiologie: Onomkeerbare verwyding van respiratoriese brongioli en alveoli agv strukturele skade.

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

Staking van rookgewoontes; immunisering teen influenza, brongodilatore vir lugwegobstruksie, sekrete - stoom verdun mukus, suurstof-inhalasie, gereelde matige oefening om longkapasiteit te verbeter.

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

Ipratropium is 'n M3 antagonis in die lugweg. Dit werk die effekte van Ach tee dus veroorsaak dit brongodilataie en verlaagde mukusproduksie. Ipratropium is kortwerkend, saldus help by akute asma, maar nie lank by KOLS nie.

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

Dit versterk die kontraksie van die diafragma skeletspiere - so verbeter dit die ventilasie respons, en verminder hipoksie en dispnee in KOLS pasiente.

• Wat is die rol van suurstofterapie by COLS?

Dit help by hipoksie. Sommige kere wanneer die siekte al redelik ernstig is, is mense op 18-24h 'n dag se suurstof-terapie. Ander mense het dit slegs tydens oefening en slaap nodig.

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. It is also the choice of means in children.

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:

Within 1-2 days: Nausea, vomiting, abdominal pain, fatigue and weakness in the beginning.

After 1-2 days: Renal impairment & hepatotoxicity occurs 24-48h after overdose with light subcostal pain, tar liver, jaundice, renal insufficiency, liver necrosis and death.

A dose of 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

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

Endothelium-dependent vasodilation is when acetylcholine and bradykinin, act by increasing intracellular calcium levels in endothelial cells, leading to the synthesis of NO. NO diffuses to vascular smooth muscle, leading to vasorelaxation. Endothelium cells respond to vasorelaxants by releasing soluble EDRF. EDRF acts on vascular muscle to cause relaxation and gives a vaso-relaxing effect. 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 are enzymes that are synthesized on a constant basis regardless of the physiological demand, so they have a greater physiological and pathological implication because they occur permanently in an area. Induced enzymes are enzymes that occur after a substance is added, so the enzyme is not present before the substance, which means that something has to be excreted by the body before that enzyme takes effect, so the implications are smaller.

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?

Nitric Oxide (NO)

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

NO is inactivated by reaction with oxygen to form nitrogen dioxide. NO reacts with superoxide to form peroxynitrite. Intracellular glutathione protect against tissue damage caused by scavenging peroxynitrite. Peroxynitrite 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.

When challenged with foreign antigen, TH1 cells synthesis Nitric Oxide, the importance of NO of TH1 cell is demonstrated by the impaired protective response to injected parasites after inhibition of iNOS. NO also stimulates the synthesis of inflammatory prostaglandins by activating COX-2. Through its effects on COX-2, its direct vasodilatory effects, and other mechanisms, NO generated during inflammation contributes to the erythema, vascular permeability, and subsequent edema associated with acute inflammation. 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? 

• Parkinson's disease, stroke and amyotrophic lateral sclerosis.

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

Studies have shown that fluvoxamine binds 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. Therefore, fluvoxamine acts as an anti-inflammatory, and may be helpful in treating covid patients who are struggling with inflammation, degenerating into their lungs.

Sigma-1 agonism has been shown to inhibit SARS-CoV-2 replication and to modulate the inflammatory response to sepsis(The medical letter, 2021). It could theoretically prevent development of life-threatening cytokine storm and acute respiratory distress syndrome in COVID-19. Fluvoxamine has shown to prevent clinical deterioration (such as shortness of breath and hypoxemia) in patients who tested positive for COVID-19 (The medical letter, 2021).

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 institue of health). 2021. https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/ Date of access: 13 Oct. 2021

NIH (National institue 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

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

• Verhoogde angiotensingeen vlakke word gesien in hipertensie sowel as hartversaking. As gevolg van die verhoogde antiotensien II vlakke weens ‘n moontlike ooraktiewe RAAS sisteem veroorsaak dit erge vasokonstriksie. Dit lei tot hipertensie, wat druk op die hart sit en hartversaking kan veroorsaak. Die ooraktiewe RAAS sisteem het ‘n aanleiding tot die verhoging in die angiotensinogeen vlakke.
• Imlikasies van hoë angiotensinogen vlakke lei tot verhoogde bloeddruk vlakke asook retensie van vloeistof in die urienwegstelsel. Verder lei dit ook tot ‘n vergrootte hart a.g.v. ventrikulêre hipertrofie.

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

• Die angiotensien antagoniste wat inwerk op die angiotensienreseptore, het ‘n direkte effek op slegs die angiotensien sisteem van die liggaam en is dus angiotensienstelsel selektief. AOE het ‘n effek om bradikinien om te skakel na die onaktiewe metaboliete toe. Die AOE remmers kan dus ook inwerk op die bradikinien stelsel. Die remming van AOE in bradikinien kan die konsentrasie van bradikinien verhoog wat inwerk op die sensoriese senu-eindpunte en pyn en ‘n droë hoes tot gevolg kan hê

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

• Eerstens, inhibeer AOE-remmers die omskakeling van angiotensin I → angiotensin II. Dit lei tot ↓ in angiotensin II produksie en veroorsaak ‘n ↓ in RAAS. Bradikinien kan nie afgebreek word nie deur AOE na onaktiewe metaboliete nie, dus bly bradikinien ‘n potente vasodilator & ↑ Prostaglandiene sintese wat lei tot vasodilatasie.
• Tweedens veroorskaak dit ‘n ↓PVR = ↓BP. Dit werk in op die Bradikinien stelsel waar dit bradikinien omskakel na sy onaktiewe metaboliet toe. Bradikinien het ‘n sterk vasodilatoriese werking. Deur die AOE te rem beteken dit dat angiotensien I nie omgeskakel kan word na angiotensien II toe nie. Dit bedoel dat dit die vasokonstriktiewe eienskap uitsluit. Die AOE remmers sal dus ook die vlakke van bradikinien verhoog in die liggaam deurdat dit nie na sy metaboliete omgeskakel word nie. Daar sal dus vasodilatasie voorkom weens die verhoging in bradikinien vlakke, daarom kan daar gesê word dat dit as ‘n tweevoudige meganisme kan gebruik word.

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

• Losartan en varsartan is selektiewe kompeterende antagoniste van angiotensin II AT1-reseptore & werk dus op AT1 reseptore. Hulle het ook ‘n meer volledige blokade van die angiotensin sisteem, dieselfde as AOE-remmers, maar daar is geen toename in bradikinien. Dit inhibeer vasokonstriksie en aldosteroon sekresie wat dus ‘n afname in bloeddruk en vasodilatasie tot gevolg het.

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

• Kiniene veroorsaak vasodilatasie van die arterieë en venas.

Ja, ander outakoïede speel ook ‘n rol in hierdie werking- hulle tree op as tweede boodskappers soos bv.  die endoteel en prostaglandiene wat vrygestel word na aktivering deur bradikinien. Dit speel ‘n rol om die deurlaatbaarheid te verhoog en gevolglik edeem kan veroorsaak.

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

• Daar is G-protein gekoppelde reseptore betrokke, maar die mees betrokke een is Bradikinien 1&2-reseptor.

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

• • Natriuretiese peptiede is effektief omdat dit vasodilatasie veroorsaak en sodoende ‘n afname in perifere weerstand & hart uitwerp wat lei tot ‘n afname in bloeddruk.  Dit word vrygestel in die atria nadat daar spanning op die hart ventrikels waargeneem is.
  • Natriuretiese peptiede verhoog ook die glomerulere filtrasie en verlaag die Na⁺ herabsorpsie, wat daartoe lei dat die bloed volume sal verlaag. H2O sal ook Na⁺ volg en edeem kan verminder tydens kongestiewe hartversaking. Natriuretiese peptiede verlaag ook die renien vrystelling wat ‘n effek op die RAAS sisteem sal hê en dus ook hipertensie kan voorkom.

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 sy aktiwiteit te inhibeer word die effekte van ANP & BNP verleng wat vasodilatasie tot gevolg het en ook ander meganismes om hartuitwerp en perifere weerstand te verlaag en lei tot natriurese & diurese. Spanning word ook op die versakende hart verlig. Die middel staan bekend as: Sacubitril en word in kombinasie met valsartan gegee. Valsartan is ‘n ACE-inhibeerder, wat artriële dilatasie veroorsaak (Soos geleer in LE 1). Die kombinasie van die twee middels word vir behandeling van hartversaking gegee.

Gee voorbeelde van endotelium-afgeleide vasodilatore en vasokonstriktore.

• Vasodilatore: PGI₂ & NO
• Vasokonstriktore: Endotelien - ET₁, ET₂, ET₃

• Migraine
• Pathology

Migraine involves the trigeminal nerve distribution to instracranial, and possibly extracranial, arteries. These nerve release peptide neurotansmitters, especially calcitonin gene-related peptide, CGRP, an extremely powerful vasodilator. Substance P and neurokinin A may also be involved. 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. A migraine is also characterized by nausea, vomiting and visual scotomas or even hemianopsia and speech abnormalities.

• Current treatment and mechanism of action:

Triptans e.g. Sumatriptan: The first line drug therapy for acute severe migraines. These drugs are selective agonist for 5-HT 1D and 5-HT 1B receptors. They activate these receptors on the presynaptic trigeminal nerve ends to inhibit the release of the vasodilating peptides. Triptans should not be used in patients with coronary artery disease because they have the ability to cause coronary vasospasms.

Lasmiditan: Is a highly selective 5-HT 1F receptor agonist and is effective in treating migraines. The agent lacks vasoconstriction actions and is a much more cardiovascular save than the triptans. The drug reduces trigeminal nerve stimulation-induced plasma and plasma protein extravasation in dura vessels. Lasmiditan is used in acute migraines.

Ergot alkaloids e.g. Ergotamine and Ergonovine: The ergot derivates have mixed partial agonist effects at 5-HT2 and at alpha adrenoceptors. These drugs cause a marked smooth muscle contraction but they also block alpha agonist vasoconstriction. These agents therefore also prevent the above-mentioned vasodilation that leads to pain.

Anti-inflammatory analgesics e.g. aspirin/ibuprofen: These drugs are helpful in controlling the pain of the migraine, but not resolving the migraine itself.