• Gee jou eie definisie van COLS.

KOLS is 'n kombinasie van 3 verskillende pulmonêre toestande naamlik, kroniese brongitis, asma en emfiseem.

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

Kroniese brongitis is ’n nonspesifieke obstruktiewe toestand wat gekenmek is deur verhoogde mukussekresie en velaagde mukosilliêre opruiming. Daar sal ook gereelde bakteriële infeksies voorkom. DIt kan herken word deur die verandering in brongiale wande en die persoon sal aanhoudend hoes oor die taai slym in die longe.

Emfiseem word veroorsaak deur rook en irritante. Dit is wanneer die brongioli en aveoli struktureel beskading is en is dus ONomkeerbaar. Die lug word vasgevang en gaswisseling kan nie plaasvind nie, dus sukkel die persoon om die lus weer uit te asem.

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

Indien die persoon rook, moet hy/sy onmiddelik ophou. Indien daar bakteriële infeksies voorkom sal die persoon antibiotika moet neem. Soms word kortikosteroiede ook bygevoeg saam met ‘n anticholinergiese middel, wat kan help met inflammasie in die longe. Indien die pasiënt slym op die bors het kan ’n verdunning ook geneem word soos ’n ekspektorant wat die slym kan verdun en maklik uit die longe verwyder kan word.

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

Brongiole asma is gekenmerk deur inflammasie, en Ipratropium is n anticholinergiese mideel wat nie anti-inflammatiese effekte het nie.

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

Dit help met kontraksie vand ie diafragma en versterk dit. Wat dus kan help met ventilasie en kan hipoksie verminder word.

• Wat is die rol van suurstofterapie by COLS?

Indien die middels soos die ₂ agoniste of die anticholinergiese middels nie 100% effektief werk nie, moet die pasiënt suurstofterapie kry.

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

Paracetamol is a weak COX-1 and COX-2 inhibtor and has no anti-inflammtory action, where Aspririn does. It is used in mild to moderate pain when an anti-inflammatory effects if not neccersary.

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

Used as antipyretic and analgesic agent. It doesn’t affect uric acid levels is not a platelet inhibitor. Used for headache, myalgia, potspartum pain. It is safe to use in pregnancy, children, patients with asthma, gout and patients who have a tendency to bleed easily.

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

Patients can develop a rash and urticaria.

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

Within 1-2 days : The patient can become nauseas and vomit, abdominal pain and decreased appetite can occur as well as feeling fatigued.

After 1-2 days : The patient may experience right subcostal pain, jaundice can appear, tar liver and can develop renal insufficiency, liver necrosis and even death.

Treating acute toxicity:

• Supplementation of -SH group to supplement glutathione in liver
• N-acetylcysteine​​ (Parvolex®) administered within 8-12 hours via IV
• Oral Treatment: acetylcysteine​ ​(Solmucol®, ACC®),140mg/kg or carboscistein (Mucosirop®, Flemex®) 150mg / kg.

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). 

Fluvoxamine is a selective serotonin reuptake inhibitor (SRRI), used in OCD (over compulsive disorder) and depression. In COVID-19 patients Fluvoxamine was found to reduce expression of inflammatory genes. In a study, when SARS-CoV-2 broke out, 65 participant who tested positive opted to take Fluvoxamine and after 14 days the patients who had lower anxiety levels, felt less fatigued and could concentrate better (NIH, 2021:204). Fluvoxamine lowers inflammatory cytokine production. It also has an antiviral effect reducing the ability to enter cells' lysosomes (Lianna Matt Mclemon, 2021:1).

• https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/
• https://www.cidrap.umn.edu/news-perspective/2021/04/ocd-drug-spotlighted-potential-covid-19-treatment

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

This means that these agents increase intracellular Ca²⁺ in endothelial cells which leads to synthesis of NO. NO diffuses into vascular smooth muscle and leads to vasorelaxation.

• 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 constantly being made whether it is need or not, they also stay is one area, where Inducible enzymes is made when a substance is present. Their effects is smaller.

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

Sepsis is caused by an infection. Edotoxin components induce synthesis of iNOS in smooth muscle cells, endothelial cells and more, which leads to widespread generation of NO, can lead to hypotension, shock and in some cases 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?

NOS inhibitors are releases which binds to L-arginine form which NO is synthesised from. This prevents arginine to bind to the three NOS enzymes, which leads to decrease concentration of NO.

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

A Stimulus can activate the inflammatory mediators, which result in increase in iNOS levels. The vasodilatory effects of NO and effects of COX II plays a role in inflammation and causes red skin, increased vascular permeability which can lead to oedema. Although a disadvantage is that excessive production of NO, causes tissue damage, diseases, asthma and lesions.

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

In stroke, amyotrophic lateral sclerosis, and Parkinson disease, where excessive NO is involved.

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

Hypertension and cardiac hypertrophy

When angiotensinogen levels increase, more angiotensinogen will be converted to ANG I by renin. ACE converts ANG I to ANG II, which then increase blood pressure, ANG II also increase aldosterone release in the adrenal cortex. ANG II also contribute to cardac hypertrophy which can lead to miocardial infarction which leads to heart failure.

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

ACE inhibitors, not only inhibit the conversion of ANG to ANG II, but also prevent bradykinin metabolism. Which leads to level of bradykinin increasing, and can acuse side effects like dry cough.

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

ACE inhibitors works in two ways, 1. Inhibiting the conversion of ANG I to ANG II, and 2. Blocking ANG II type 1 receptors. This causes vasoconstriction, decreasing peripheral resistance and lowering blood pressure. Aldosterone levels decrease, leading to less salt and water retention which decrease CO, cardiac preload and lower blood pressure. ACE inhibitors also prevent bradykinin metabolism which can lead to increased levels of bradykinin and increase arterial vasodilation, lower PR and lowers 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 and similar drugs are competitive antagonists at angiotensin AT₁ receptors, but has no effect of angiotensin 2 receptors.

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

Kinins produce arteriolar dilation which is an effect of kinins on arteriolar smooth muscle mediated by nitrite oxide of vasodilation prostaglandins. Kinins causes contraction in veins due to contraction in visceral smooth muscle.

• 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 causes vasodilation that leads to decrease in PR and lowers blood pressure in patients with hypertension. These peptides also increase glomerular filtration which leads to more sodium excretion and decreasing sodium reabsorption, thus treating oedema that is 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 metabolises natriuretic peptides, inhibiting Neprilysin leading vasodilation of ANP and BNP level increase and increase in renin secretion leading to higher levels of ANG II, helping in treatment of heart failure. 

Drug name: Sacubitril

• Give examples of endothelium-derived vasodilators and vasoconstrictors. 

Vasodilators: Bosentan, macitentan, ambrisentan, sitaxsentan.

Vasoconstrictors: Endothelin 1,2,3

Migraine involves the trigeminal nerve distribution to intracranial arteries. These nerves release neurotransmitters like calcitonin (a vasodilator). The vasodilation and stretching caused by perivascular edema may be the cause of migraine. Relieve of a migraine can be by therapy of diminution of these pulsations.

 

Sumatriptan is first in line to treat acute severe migraine, because it’s a generic and much cheaper than the other -triphans, and should not be used in patients with coronary artery disease because it can cause discomfort and pain in chest. Anti-inflammatory anagelsics such as Aspirin and Ibuprofen can also be used. For patients with severe nausea and vomiting, can parenteral Metoclopramide be used. Almotriptan, Rizatriptan and Zolmitriptan can also be used but they do have a short duration of effect. Naratriptan and Eletriptan, Frovatriptan and Zolmitriptan can also be used but have some contraindications.

 

Lasmiditan is also used for antimigraine. It has the affinity for 5-HT receptors, it does not cause vasoconstriction and is thus safer than triptans regarding cardiovascular system. It reduces trigeminal nerve stimulation-induces plasma and plasma protein extravasation in dural vessels. Erenumab and Ubrogepant binds to CGRP receptors and prevents activation by peptides, and treat acute migraine attacks. Propanalol, Amitriptyline and some Ca²⁺ blockers can also be used in migraines. Flunarizine (Ca²⁺ blocker) reduce the severity of an acute attack. Verapamil have also been effective.