Exercise 1

Study section 2.7a

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

• Selective inhibitor of micro-tubules and spindle formation in macrophages and leukocytes (thus inhibiting mitosis)
• Also inhibits chemotaxis
• Decreases leukocyte metabolism, thus reducing lactic acid formation and increasing pH.

2. 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.

Indications: acute gout arthritis

Side effects: GIT discomfort, diarrhea, nausea, abdominal pain, Gastric bleeding at high dose, Liver damage, Kidney damage, Bone marrow suppression, Peripheral neuritis, Alopecia

Dose: 0.5 – 1 mg immediately, followed by 0.5 mg every 6 hours until pain relief or gastric discomfort is reached. Max: 2.5 mg in first 24 hours • No more than 6 mg over 4 days • Course may not be repeated within 3 days

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

• NSAID’s= Indomethacin, Diclofenac, Piroxicam, Naproxen
• Glucocorticoids =Prednisone, Betamethasone

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

Uricosuric drugs . It act by increasing uric acid secretion.

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

Irreversible Xanthine oxidase inhibitors • Reduces the conversion of xanthine to uric acid, thus reducing the production of uric acid • Allopurinol therefore increases [xanthine] and [hypoxanthine], both of which are more water soluble than uric acid • Precursors therefore easily excreted and lower [uric acid]

Avoid in acute gout attack

 

Exercise 2

Study section 2.7b

1. Which vascular changes can be observed before and during migraines?

Before migraines their is vasoconstriction and after migration their is vasodilation.

2. What is the role of serotonin in migraine headaches?

• Activation of 5-HT1B receptors causes vasoconstriction of cranial arteries that are painfully dilated during acute migraines.
• Activates 5HT1D receptors on presynaptic trigeminal nerve endings to inhibit neuroactive vasopeptide release and block the transmission of pain impulses to the brain

3. How is ergotamine used during a migraine attack?

acute treatment. Only effective if taken with first signs of migraine. 5-HT1D partial agonist, causes direct vasoconstriction (especially of intracranial arteries)

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

Side effects: • Nausea and vomiting • Diarrhea • Hallucinations and confusion • Gangrene • Retroperitoneal fibrosis • Tachycardia / bradycardia, angina pain • Regular headache back pain • Contraindications: • Coronary, cerebral and peripheral vascular diseases • Uncontrolled hypertension • Hepatic and renal impairment • Pregnancy • Combination with triptans

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

Analgesia: Paracetamol, NSAID’s, Aspirin • Anti-emetics: Metoclopramide, Domperidone, Cyclizine • Ergotamine • 5-HT1D agonist: Sumatriptan, Zolmitriptan, Eletriptan, Naratriptan, Rizatriptan • Sedative drugs: Diazepam

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

Betablockers: Propranolol • α2- agonist: Clonidine • Ca2+ blockers: Flunarizine, • Tricyclic antidepressants: Amitriptyline • Anticonvulsant: Valproate, Topiramate • 5-HT2 antagonist: Pizotifen

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

The concept that the endothelium controls vascular tone in a paracrine fashion  was extremely innovative and relevant to vascular physiology. Numerous endothelium-dependent vasodilators, such as 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.

When we talk about the 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. 

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". it has small effects.

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

This physiological production of NO is important for blood pressure regulation and blood flow distribution. Several lines of evidence suggest that a hyperproduction of NO by the inducible form of NO synthase (iNOS) may contribute to the hypotension, cardiodepression and vascular hyporeactivity in septic shock.

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 enzyme inhibitors is release by our body, that competitively bind to the binding site of arginine  in NOS. (arginine is not converted to nitric oxide)

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. NO is  synthesized (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.

In which possible neurological and psychiatric diseases is NO involved? 

Parkinson's disease

stroke

amyotrophic lateral sclerosis

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 may prevent clinical deterioration by stimulating the σ-1 receptor, which regulates cytokine production.

In a murine sepsis model, fluvoxamine was found to bind to the sigma-1 receptor in immune cells, resulting in reduced production of inflammatory cytokines. In an in vitro study of human endothelial cells and macrophages, fluvoxamine reduced the expression of inflammatory genes. Further studies are needed to establish whether the anti-inflammatory effects of fluvoxamine observed in nonclinical studies also occur in humans beings and are clinically relevant in the setting of COVID-19.

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

Weak COX-1 and COX-2 inhibitor peripheral. Blocks COX-3 in CNS, activating declining serotonergic analgesic pathways. Antipyretic: direct action on hypothalamic thermoregulation center. it has no anti-inflammatory where asprin has.

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

Adults : Acute pain: 325mg - 1000mg 4 times a day. Not more than 4 g in 24 hours (acute liver failure, skin rash: Stevens-Johnson) . Chronic pain: less than 2 g (4 tablets) per 24 hours.

Children: 10mg/kg/dose (or according to manufacturers' directions by age) 

only low doses is safe, high doses is very toxic.

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

• low fever with nausea, stomach pain, and loss of appetite;
• dark urine, clay-colored stools; or.
• jaundice (yellowing of the skin or eyes).

4. 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.

if you use paracetamol adjustments required in: • Alcoholics • Liver –and kidney diseases • Anaemia (less glutathione). Misplaced safety delusion: 10-15g (so 20-30 tablets) can be fatal • Chronic use of 2g / day can also lead to paracetamol poisoning. • Combination of analgesics may increase toxicity.

Within 1-2 days: Nausea and vomiting Abdominal pain Decreased appetite Tired and powerless

After 1-2 days: Right subcostal pain Tar liver Jaundice Renal insufficiency occurs Liver necrosis and death

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

Increased angiotensin II levels are central in hypertension, dyslipidemia, and insulin resistance, which, taken together with obesity, represent the metabolic syndrome. Increased Ang II levels contribute to hyperfiltration, glomerulomegaly, and subsequent focal glomerulosclerosis by altering renal hemodynamics via afferent arteriolar dilation, together with efferent renal arteriolar vasoconstriction as well as by its endocrine and paracrine properties linking the intrarenal and the systemic RAAS, adipose tissue dysfunction, as well as insulin resistance and hypertension

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

ACE inhibitors influence bradykins and angiotension II and the Angiotension inhibitors only influence angiotension.

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

ACE inhibitors are considered to have a two-fold mechanism of action in treatment of hypertension, as these inhibitors prevent the conversion of:

Angiotensin I to angiotensin II, thus inhibiting the release of aldosterone. Aldosterone-release inhibition promotes water and salt excretion, decreasing fluid volume and eventually blood pressure. Bradykinin to an active metabolite. Bradykinin is a vasodilator which widens the blood vessels allowing easier flow of blood, eventually decreasing blood pressure. 

4. 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 is an angiotensin II receptor blocker and is used to treat hypertension. Losartan competitively prevents angiotensin II binding to the AT₁ receptor in tissues like vascular smooth muscle and the adrenal gland. Losartan and its active metabolite bind the AT₁ receptor with more affinity than they bind to the AT₂ receptor, thus having a direct effect on the angiotensin II receptors.

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

They dilate the arteries and veins. Other autocoids like nitric oxide or vasodilator prostaglandins (PGE₂ & PGI₂) can also play a role in this action by acting as mediators.

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

Beta-2-blockers

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

They cause a compensatory increase in renin secretion and plasma angiotensin 2 levels, which will then reduce blood pressure and help in the treatment of hypertension. In heart failure, they cause vasodilation and natriuresis.

8. 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. 

Neprilisien is 'n ensiem wat natriuretiese peptiede afbreek. Sacubitril wat 'n neprilisien inhibeer is word saam met Valsartan gebruik vir behandeling van hartversaking. 

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

• NO (Nitric Oxide) is an endothelium-derived vasodilator.
• ET-1 is an endothelium-derived vasoconstrictor.

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