• Briefly explain what cystic fibrosis is and how dornase alpha works to solve the problem

Cystic fibrosis is a genetic defect where organ secretions are drastically reduced (Dnase I is reduced) In the airways it causes serious problems as mucosal secretions become very thick and create the ideal environment for bacterial infections. The persistent infections cause incessant chemotaxis of neutrophils which then deposit DNA in the mucus making it even tougher.

Dornase alpha hydrolyzes extracellular DNA from the neutrophils in the bronchial mucus and thus causes a drastic decrease in the toughness of the mucus. Its feasibility increases.

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

The surfactant that covers the respiratory unit of the airways is formed only in the last weeks of pregnancy. If babies are born prematurely, this surfactant is not yet fully developed and gas exchange becomes difficult / lungs fall flat.

Cortisone stimulates endogenous surfactant production. A short-term course can be given. If there is an imminent miscarriage, betamethasone IM can be administered to the mother just before labor and it will induce endogenous surfactant production within 24 hours.

Exogenous surfactants: these drugs are administered to the neonate using a catheter into the lungs prophylactically or during acute respiratory distress syndrome, to supplement lung surfactant.

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

Oxygen therapy provides adequate oxygenation to prevent hypoxia, improve respiration, and keep alveoli open.

Excessive oxygen can cause paradoxical hypoxia, diminished gas exchange and, in extreme cases, death. In neonates, it can cause retinal damage and blindness.

• Briefly explain what neonatal apnea is and how the methylxanthine works to solve the problem. Which methylxanthines are used?

Neonatal apnea is when the respiratory center in the medulla is not yet fully developed and is not yet as sensitive to the stimulation of carbon dioxide. Premature babies in this case cannot constantly breathe properly.

Methylxanthines, ie caffeine and theophylline stimulate the central nervous system to solve the problem. It is IV administered and therapy is discontinued as soon as possible.

• Give your own definition of COLS

COLS is a chronic obstructive airways disease characterized by limited airflow through the lungs, difficult breathing, hypoxia, cough and sleep disorders. There are currently 3 conditions that can be linked to COLS, viz. Bronchial asthma, Chronic bronchitis and Emphysema.

• Briefly describe the proposed etiology and pathophysiology of chronic bronchitis and emphysema

Chronic bronchitis: The etiology is still unclear, but it appears to be caused by long-term exposure to irritants such as cigarette smoke, dust and irritating gases. It is characterized by coughing, excessive mucus secretions, decreased mucosal clearance, increase in the incidence of bacterial airway infections and structural changes in the bronchial wall. Chronic bronchitis is associated with an overactive parasympathetic nervous system as it induces the vagus reflex of irritant receptors in the airways.

Emphysema: It is the irreversible dislocation of the bronchioli and alveoli that causes air to be trapped in the respiratory spaces of the lungs, but is very difficult to exhale. There is also reduced blood flow through the capillary blood vessels which further complicates gas exchange. It is very strongly associated with cigarette smoking from heavy smokers and genetically susceptible individuals

• What types of therapy are included to treat a COLS patient?

A step-by-step approach to therapy is used:

Anti-cholinergic therapy serves as the first line of therapy: Ipratropium inhalation is usually indicated

If the anti-cholinergic therapy is not sufficient, it can be used in combination with a Beta2 agonist and / or a slow-release form of theophylline

If necessary, additional oxygen therapy can be added

Oral / inhalation therapy of corticosteroids may also be added if no. 2 is not sufficient

With acute disease: Hospitalization with maximal bronchodilator and systemic corticoid therapy, physiotherapy, oxygen and if necessary: ​​antibiotics

• Why is ipratropium more effective in treating chronic bronchitis than in treating bronchial asthma?

Ipratropium is an anti-cholinergic agent which therefore cooperates with the parasympathetic nervous system. It is an M3 receptor antagonist in the airways. Chronic bronchitis is associated with an overactive parasympathetic nervous system, as it mediates the vagus reflex that types are induced after stimulation of airway irritant receptors. Ipratropium therefore counteracts this effect. While in bronchial asthma inflammatory conditions are central, for which Ipratropium will be ineffective.

• In what ways do the skeletal muscle effects of theophylline have benefits in the treatment of COLS?

Theophylline causes increased diaphragm contractility which means it improves ventilatory capacity

• What is the role of oxygen therapy in COLS?

In severe cases of COLS, hypoxia is a serious problem. 18-24 hours / day oxygen inhalation therapy improves morbidity and mortality. In some cases, some patients only need oxygen therapy before exercise or during sleep

• How does colchicine work in the treatment of gout-arthritis?

Colchicine is quickly absorbed after administration; it reaches its peak plasma level within 2 hours. Colchicine will relieve the pain and inflammation of gout-arthritis. Colchicine gets its anti-inflammatory effect by binding to the intracellular protein tubulin. Because colchicine binds to tubulin, it inhibits the micro-tubules and leads to the inhibition of leukocyte proliferation and macrophages. Colchicine also inhibits chemotaxis which is the movement of leukocytes to the area of ​​inflammation.

• What are colchicine's indications, side effects and dose? In particular, make sure that you know exactly how to use colchicine during an acute gout attack.

Colchicine is indicated for gout and work also for gout attacks for longer periods for prophylaxis. Prolonged use for prophylaxis requires a very low dose of colchicine. Colchicine also prevents acute attacks of “Mediterranean fever” and has a moderately beneficial effect in sarcoid arthritis and in hepatic cirrhosis. Collagen can also be used to treat and prevent pericarditis, pleurisy, and coronary heart disease due to its anti-inflammatory effects. Colchicine causes indigestion, diarrhea, nausea and stomach pain. Hepatic necrosis, acute kidney damage, disseminated intravascular coagulation, and epileptic seizures have been noted. Coal vision can also cause alopecia and bone marrow suppression to a lesser extent as well as peripheral neuritis, myopathy and in some cases death. The more serious side effects were noticed by coagulated intravenously. With an acute attack, the patient can take 0.5 to 1 mg immediately, followed by 0.5mg every 6 hours until pain relief or gastric discomfort develops. Maximum of 2.5mg in the first 24 hours. The patient should not use more than 6mg over 4 days. The course may not be repeated within 3 days. For prophylaxis, the spot view should lower how serum uric acid levels are brought about. Then the patient will be able to be given 0.5mg colchicine 1-2 times a day to urate-reducing drugs.

• What other drugs can be used in the treatment of an acute gout attack?

For the acute gout attack, non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids may be co-administered with colchicine.

• What is probenecid classified as? How does this group of drugs work?

It is a Uricosuria drug. This group of drugs inhibits the active transport mechanism for the reabsorption and secretion in the proximal tubules in the kidney. The net reabsorption of uric acid must therefore decrease in the proximal tubules. If the urinary excretion of uric acid increases, the size of the urate pool will decrease. Urate will be reabsorbed which then gives the relief of arthritis. But with the increased excretion of uric acid, kidney stones can form and to prevent this we need the pH of the urine above 6.0 and therefore we need to give the patient a urine alkalizer to use with the probenecid.

• How does allopurinol work, what are its indications, precautions and important interactions?

Allopurinol is irreversible xanthin oxidase inhibitors. It reduces the conversion of xanthine to uric acid. By inhibiting the conversion, there will therefore be less uric acid production. The Xanthine concentration and hypoxanthine concentration are increased by Allopurinol. Both of these concentrations are more water soluble than uric acid. The honor water-soluble product is excreted first and thus the uric acid concentration in the body is lowered. A precaution is that if you give a chemotherapeutic purine together with an allopurinol, the dose will have to be reduced by 75%. Allopurinol may also increase the effects of cyclophosphamide. Allopurinol inhibits the metabolism of probenecid and oral anticoagulants and it can also increase hepatic iron concentrations. Safety in children and pregnant women has not yet been established.

• What vascular changes can be observed before and during migraines?

The trigeminal nerve spreads to the intracranial arteries. The nerves release peptide neurotransmitters, especially the calcitonin no related peptide (CGRP). Here peptide is a potent vasodilator. Substances A and Neurokinin A are also involved. Due to a leak, plasma and plasma proteins may be present in the perivascular space causing edema. Due to the stretching of the edema, it will activate pain nerve endings in the duration. 

• What is the role of serotonin in migraine headaches? 

Serotonin can play two roles in the treatment of migraines. The first one is the activation of the 5-HT1B agonist causing vasoconstriction of the cranial arteries. During the acute migraine the arteries dilate and it is very painful but the serotonin constricts the artery. The second one is the activation of the 5-HT1D receptors on the presynaptic trigeminal nerve endings. The activation will result in inhibiting vasopeptic (CGRP) release and because the transmission is then interrupted, pain message will not be able to go to brain and the vasodilation effect cannot continue because it is suppressed.

• How is ergotamine used during a migraine attack? 

It should be taken with first signs of migraine to be effective for an acute migraine attack. It can also be used in combination with caffeine. The ergotamine should be used with caution as it has many side effects. Dosage: Take 1 tablet with first warning of attack. Then take 0.5 to 1 tablet every 30 min as needed. A maximum of 4 tablets may be taken in a migraine attack and a maximum of 6 tablets may be taken per week.

• What side effects are experienced with ergotamine use? 

What contraindications are there for ergotamine use? Ergotamines have many side effects. Nausea and vomiting, Diarrhea, Hallucinations and confusion, Gangrene, retroperitoneal fibrosis, or bradycardia and angina pain. Relapse headaches can also happen with regular use. Ergotamines cannot be used if the patient has any blood vessel diseases such as coronary, cerebral, and peripheral vascular diseases. It is contraindicated if the patient's hypertension is uncontrolled if he / she has hepatic and renal impairment. Absolutely contraindicated is pregnancy and it can also not be used with any triptans at all.

• What other drugs can be used in an acute migraine attack? How do all these drugs work?

Other treatments that can be used for migraines besides ergotamines and serotonin agonists are analgesics such as paracetamol, non-steroidal anti-inflammatory drugs and aspirin. Antiemetics such as metoclopramide, domperidone and cyclicin can also be given and finally sedatives such as diazepam can be given. Analgesics are used as the first line medication in a migraine attack. The medication will relieve the pain of mild to moderate migraines. Because nausea and vomiting occur very frequently with a migraine attack, we will give you an anti-emetic to relieve the nausea and vomiting. Cyclicin is an H1 antagonist that blocks antimuscarinic activity in the vomiting center. The metoclopramide and domperidone are D2 antagonists and an advantage of both is that they are prokinetic. Because sedatives are habit-forming, they are not widely used but when used they are due to muscle relaxation and sedation.

• Name the drugs that can be used as migraine prophylaxis, as well as their specific side effects and precautions. 

There are 6 drugs that can be used as prophylaxis. 

1. Beta-blockers- Some of the side effects are bradycardia, drowsiness, depression, sexual dysfunction and nightmares. Precautions are that pregnant and breastfeeding woman can not use edit. People with a liver or kidney problem should also be careful, it is also forbidden in some sports. 

2. Anticonvulsants- Some of the side effects are paresthesia, dizziness, fatigue, nausea, anorexia, drowsiness and memory problems Precautions are again for pregnant and breastfeeding women. Babies can be born with cleft palate. Patients with kidney problems should also be careful. 

3. Ca + 2 antagonists- Some of the side effects are drowsiness, depressive and weight gain. 

4. Tricyclic antidepressants- One of the side effects is that it can make you drowsy know a precaution is that it is administered in low doses for migraines. 

5. 5-HT2 antagonists- Sedation, Increased appetite weight gain, vision disorders urinary retention and dry mouth. A precautionary measure is that it may not be used in pregnancy or breastfeeding, even if you have a spinal or kidney problem.

6. A2 agonist- Some of the side effects are that it may aggravate depression and cause insomnia. The precautions are that pregnant and breastfeeding woman may not use edit and if you have a kidney restriction should not use.

• What is the mechanism of action of paracetamol? How is it different from that of aspirin?

Paracetamol is a weak cyclo-oxygenase (cox) COX 1 and COX 2 inhibitor in the peripheral
tissue. This is why it does not show anti-inflammatory effects. Paracetamol also inhibits the
COX 3 enzyme located in the central nervous system. If the COX 3 is blocked, it will activate the decreasing serotonergic analgesic pathways. Paracetamol is also antipyretic because it works directly on the hypothalamic thermoregulation center and then lowers the fever. 
Aspirin is an irreversible, non-selective COX 1 and COX 2 blocker. It lowers prostaglandin,thromboxane and prostacyclin production in the body. Aspirin is then also used to lower 
platelet adhesion, it is also antipyretic, analgesic and then has hyo ok anti-inflammatory 
effects.

• Name the indications for paracetamol. In what circumstances is it a preferred remedy in the treatment of moderate pain and fever?

Although it is said that aspirin and paracetamol are the same, it is completely wrong. 
Paracetamol does not have anti-inflammatory or anti-platelet adhesion properties. 
Paracetamol is useful for use in mild to moderate pain such as headaches, postpartum 
pain and myalgia where aspirin is also an effective analgesic. Paracetamol is also 
recommended for use in moderate pain if the patient is allergic to aspirin. A patient with a peptic ulcer and someone who has aspirin tightened his chest will also need to use paracetamol for pain and fever, as well as a patient who tends to hemophilia.

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

Nausea and vomiting, constipation and abdominal pain, skin rash and urticaria and acute 
liver failure and jaundice. Bloody, black stools and dark urine.

• Due to the readily available paracetamol availability and the general public perception that paracetamol is a very safe drug, paracetamol poisoning (accidental / intentional) is fairly common. Compile a report discussing acute paracetamol toxicity with emphasis on dose, signs and symptoms and treatment. In your textbook, as well as in the SAMF, there is valuable information you can use.

The liver enzymes catabolize conjugation of paracetamol. When the enzymes are saturated, toxic NAPQI forms. NAPQI is deactivated by glutathione BUT if glutathione levels are 
depleted it causes NAPQI necrosis.in the liver and kidney tubes. A fatal dose can be 10-15g per day.This is between 20 and 30 tablets. If a patient experiences a lot of pain and 
thinks that paracetamol is very safe, someone can very easily take so many pills for pain 
and not even realise how toxic it is. The normal adult dose is only 4g per day. 
Unfortunately, the symptoms of paracetamol poisoning take a long time and you can only 
experience nausea and vomiting, stomach pain, decreased appetite, fatigue and 
weakness within 1-2 days after the overdose. After 1-2 days the big trouble comes and 
you may experience symptoms like right subcostal pain, tender liver and jaundice. Then 
renal insufficiency can occur, then liver necrosis and then death. The treatment of acute 
toxicity should happen vining. The treatment for acute toxicity is poorly effective for the first10 hours after poisoning. Within the first hour after poisoning, you should try to induce 
vomiting, you can do a gastric lavage and one can use activated carbon as IV treatment, 
The patient needs immediate supplementation of the sulfhydryl group to produce 
glutathione in the liver fill to prevent liver cell necrosis - acetylcysteine ​​should be 
administered in IV within 8-12 hours. The initial dose is 150mg / kg in 200ml 5% glucose 
over 15 minutes, then 50mg / kg in 500ml 5% glucose over 4 hours and then 100mg / kg in1000ml 5% glucose over the next 16 hours. 
Oral treatment can also be administered by acetylcysteine ​​at 140mg / kg or carbocystine 
at 150mg / kg.

• Give a brief and critical explanation of the rationale for using fluvoxamine (a selective serotonin reuptake inhibitor (SSRI) in the treatment of Covid patients. Your answer should include appropriate references as well as in-text references.

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) used in a study to investigate clinical deterioration in patients with mild to moderate coronavirus disease. (Reiersen et al., 2021) Fluvoxamine also has affinity for the α1 agonist receptor. (Narita et al., 1996) It controls inflammation. The effects that fluvoxamine or other SSRI products have that can help with kovid-19 patients are decreased platelet aggregation, regulation of inositol enzyme, 1a-driven inflammation, and elevated melatonin levels, which have a direct antiviral effect. It also regulates coagulopathy or a mild cytokine storm, which is very dangerous in severe covid 19 cases. (Reiersen et al., 2021) Inflammatory cytokine activity and no expression are regulated by Fluvoxamine in both human and animal models of inflammation (Taler et al. al., 2007) The potential of fluvoxamine on the cytokine storm in covid 19 patients is there. The severity of the covid 19 infection is due to how the inflammation in the body increases as well as the cytokines and chemokines (Reiersen et al., 2021) Platelet aggregation is also a problem is covid 19 patients. Platelets do not possess the enzyme that synthesizes serotonin (Ni and Watts, 2006). If thrombosis occurs, serotonin will be released through platelet aggregation using hemostasis (Reiersen, 2021). As a result, the SSRI can reduce the bleeding time, which indirectly means a reduced platelet adhesion (Ni and Watts, 2006).

 Narita, N., Hashimoto, K., Tomitaka, S.I., and Minabe, Y. (1996). Interactions of selective serotonin reuptake inhibitors with subtypes of σ receptors in rat brain._ _Eur. J. Pharmacol. 307 (1), 117–119. doi:10.1016/0014-2999(96)00254-3 

Ni, W., and Watts, S. W. (2006). 5-hydroxytryptamine in the cardiovascular system: focus on the serotonin transporter (SERT). Clin. Exp. Pharmacol. Physiol. 33 (7), 575–583. doi:10.1111/j.1440-1681.2006.04410.x 

Reiersen, AM., Sukhatme, VP., Sukhatme, VV., and Vayttaden, SJ. (2021) Fluvoxamin: A Review of its Mechanism of Acion and Its Role in Covid-19. Frontiers in Pharmacology https://doi.org/10.3389/fphar.2021.652688

Taler, M., Gil-Ad, I., Korob, I., and Weizman, A. (2011). The immunomodulatory effect of the antidepressant sertraline in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Neuroimmunomodulation 18 (2), 117–122. doi:10.1159/000321634

• 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. Activation of ET-B1 receptors on the endothelium causes vasodilatation by inducing the release of NO and PGI2. In ED, ET-B1 receptors on the endothelial cells are downregulated, while ET-B2 receptors on smooth muscle cells are upregulated, thus enhancing vasoconstriction

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

An adaptive enzyme or inducible enzyme is an enzyme that is expressed only under conditions in which it is clearly of adaptive value, as opposed to a constitutive enzyme which is produced all the time. The Inducible enzyme is used for the breaking-down of things in the cell. Constitutive enzymes are maintained at constant concentration, without regard to metabolic need or substrate concentration. Their role in maintaining cell processes or structure is critically important, so they are never “off.” Inducible enzymes are not maintained at a constant concentration but are induced to be manufactured only when substrate is available.

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

In human septic shock, inhibition of NO synthesis has been shown to alter hemodynamic variables. excessive production of NO leads to severe hypotension and may cause signs of shock.

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

Natriuretic peptide

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

Nitric oxide (NO) is a signaling molecule that plays a key role in the pathogenesis of inflammation. It gives an anti-inflammatory effect under normal physiological conditions. On the other hand, NO is considered as a pro-inflammatory mediator that induces inflammation due to over production in abnormal situations.

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

Autism, OCD

• Why do you think aspirin is contraindicated in people with allergic asthma?

Some people with asthma cannot take aspirin or NSAIDs because of what’s known as Samter’s triad -- a combination of asthma, aspirin sensitivity, and nasal polyps. NSAIDs, including aspirin, possibly cause asthma exacerbations, particularly in patients allergic to these drugs. Aspirin/NSAIDs inhibit cyclooxygenase (COX) and reduce prostaglandin synthesis, thereby reducing fever and relieving pain and inflammation. Prostaglandins are responsible for the initiation of the allergic reaction.

• 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 is an essential fatty acid and a precursor in the biosynthesis of prostaglandins,thromboxanes, and leukotrienes. The stimulation of specific cell-surface receptors activates phospholipase A2 leading to the release of arachidonic acid from the cell membrane. The arachidonic acid is then rapidly converted into active metabolites by cyclooxygenases to produce prostaglandins, prostacyclin and thromboxane, and by lipoxygenase to produce leukotrienes.

• Apart from prostanoids and leukotrienes, which other non-eicosanoid product of cell membrane hydrolysis is strongly involved in asthma?

Arachidonic acid

• Why would you say a COX II-inhibitor, and not a COX I-inhibitor, has a selective action in inflammatory reactions?

COX-2 inhibitors are NSAIDs that selectively block the COX-2 enzyme. Blocking this enzyme inhibits the production of prostaglandins by the COX-2 which is mostly the cause of the pain and swelling of inflammation and other painful conditions.

• Give an example of the following:
• A drug that inhibits each of the following enzymes: phospholipase A; cyclooxygenase; lipoxygenase,

Dexamethasone

• A drug that can act antagonistically or agonistically at prostaglandin and leukotriene receptors.

Arachidonic acid

• Aspirin inhibits platelet aggregation because it inhibits thromboxane synthesis and not prostacyclin synthesis. How does it happen?

Low-dose aspirin (81 mg) inhibits the enzyme Cox-1, which is responsible for producing thromboxane A-2, necessary for platelet aggregation. Thromboxane is required to facilitate platelet aggregation and to stimulate further platelet activation

• How is alprostadil advantageous in the treatment of congenital heart defects?

Infusion of alprostadil (PGE1) dilates the ductus, increases pulmonary blood flow, and thereby improves oxygenation. Infants with aortic arch interruption or coarctation of the aorta are dependent on an open ductus to maintain lower body perfusion, hence Alprostadil has advantageous effects.

• How is misoprostil of value in the treatment and prevention of gastric ulcers?

Misoprostol is a synthetic prostaglandin E1 analog that inhibits basal and nocturnal gastric acid secretion through direct stimulation of prostaglandin E1 receptors on parietal cells in the stomach. Synthetic prostaglandins such as misoprostol given orally "replace" the prostaglandins whose production is inhibited by NSAIDs and have been shown to protect the lining of the stomach from NSAID-induced ulcers.

• Prostaglandin is possible of value in asthma. Which PGE2- or PGF2A-analogues will be effective in such a case?

Prostaglandins play a role in the pathogenesis and treatment of asthma. The E prostaglandins are potent bronchodilators, whereas the F compounds are bronchoconstrictors. In addition, PGE2 prevents bronchoconstriction induced by agents such as histamine, serotonin, bradykinin, and acetylcholine.

• How is latanoprost of value in the treatment of glaucoma?

It lowers pressure inside the eye that is caused by open-angle glaucoma or ocular (eye) hypertension. Latanoprost works by increasing the outflow of fluid from the eye. This lowers the pressure in the eye. Hence, the intra-ocular pressure is decreased by increasing the outflow of fluid.

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

Too much angiotensin II is a common problem resulting in excess fluid being retained by the body and, ultimately, raised blood pressure. This often occurs in heart failure where angiotensin is also thought to contribute to growth in the size of the heart.

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

An advantage of ARBs over ACE inhibitors is fewer adverse effects: in general, ARBs are better tolerated than ACE inhibitors. There are also ethnic differences in the risks of adverse reactions to these medications. African Americans have a higher risk of developing angio-edema with ACE inhibitors compared with the rest of the US population, and Chinese Americans have a higher risk than whites of developing cough with ACE inhibitor.

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

ACE inhibitors and bradykinin

ACE is also involved in the breakdown of bradykinin, a vasodilator. ACE inhibitors block the breakdown of bradykinin, causing levels of this protein to rise and blood vessels to widen (vasodilation) which aids to treat hypertension.

ACE inhibitors and the RAAS system

ACE inhibitors work by interfering with the body’s renin-angiotensin-aldosterone system (RAAS). RAAS is a complex system responsible for regulating the body's blood pressure. The kidneys release an enzyme called renin in response to low blood volume, low salt (sodium) levels or high potassium levels. Angiotensinogen, which is Renin catalytically cleaves these circulating angiotensinogen and forms angiotensin I. Angiotensin-converting enzymes then convert angiotensin I to its physiologically active form, angiotensin II. Angiotensin II causes contraction of the muscles surrounding blood vessels, effectively narrowing vessels and increasing blood pressure. It also stimulates the release of aldosterone, which stimulates water and sodium reabsorption, thereby, increasing blood volume and blood pressure.

ACE inhibitors stimulate the dilation of blood vessels by inhibiting the production of angiotensin II. The major organs that ACE inhibitors affect are the kidney, blood vessels, heart, brain, and adrenal glands. The inhibitory effects lead to increased sodium and urine excreted, reduced resistance in kidney blood vessels, increased venous capacity, and decreased cardiac output, stroke work, and volume.

Synthesized in the liver, is the main substrate for renin.

• 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 antagonist (AIIRA) with antihypertensive activity due mainly to selective blockade of AT1 receptors and the consequent reduced pressor effect of angiotensin II.

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

Kinins are not involved in the regulation of systemic blood pressure but participate in other aspects of arterial physiology, especially flow-mediated vasodilatation, a critical feature of arterial function, which is endothelium mediated, ensuring the proper delivery of blood to organs.

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

Kinins induce inflammatory responses via inducible B1 and constitutive B2 receptors in injured tissues

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

Many medications used to treat heart failure (e.g., diuretics such as spironolactone [Aldactone], angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers) reduce natriuretic peptide concentrations. Pharmacological natriuretic peptide augmentation lowers blood pressure. Less recognized is the fact that natriuretic peptides potently affect lipid and glucose metabolism. Through these metabolic actions, natriuretic peptides may provide a pathophysiological link between cardiovascular and metabolic disease.

• 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 neutral endopeptidase and its inhibition increases bioavailability of natriuretic peptides, bradykinin, and substance P, resulting in natriuretic, vasodilatory, and anti-proliferative effects. (Valsartan/sacubitril) is a first-in-class angiotensin II-receptor neprilysin inhibitor.

• Give examples of endothelium-derived vasodilators and vasoconstrictors.

The endothelium releases various vasoactive factors. These can be vasodilatory factors such as nitric oxide (NO), prostacyclin (PGI2) and endothelium derived hyperpolarizing factor (EDHF) or vasoconstrictive factors such as thromboxane (TXA2) and endothelin-1 (ET-1).

MIGRAINE PATHOLOGY & CAUSES: 

• Disease characterised by one sided headache (pain). There is a connection between vasodilators/vasoconstrictors and migraine. Drugs that cause vasodilation aren’t necessarily the culprits which precipitate migraines, especially if we take into consideration that anti-inflammatory drugs which have no direct vasoactive action, are also effective. Migraines aren’t simply caused by vasodilation within the brain as other drugs that do not have any direct vasoconstriction effects are still able to help with migraines. The pathophysiology of migraines are still poorly understood. The main culprits that have been identified to cause migraines involve trigeminal nerve distribution to intracranial arteries. The nerves release CGRP that are extremely powerful vasodilators. This most likely increases the intracranial pressure to such an extent that the “swelling” in the brain leads to pain, nausea, vomiting, visual scotomas. Medications that may help with migraine are in a large variety. Triptans, ergot alkaloids, NSAID’s, Beta blockers, Calcium channel blockers, tricyclic antidepressants, SSRI’s and several antiseizure agents all have a diminishing effect on migraines. Some of these drugs can only be used to prevent a migraine attack, or as a prophylactic, whilst others can be used during an attack.
• There are 2 hypotheses so far as to how these medications lessen the effects of migraines. The first one is that medications that fall under the classification as ergot alkaloids, triptans and antidepressants might activate the very specific serotonin receptor (5-HT1D/1B). This receptor can be found on the presynaptic trigeminal nerve ending. By agonizing the receptor – you inhibit the release of vasodilating peptides that would’ve led to increased intracranial pressure. Anti-seizure agents may suppress the excessive firing of these nerves. The second hypothesis argue that the direct vasoconstrictive effects of direct serotonin (5-HT) receptors may prevent vasodilation and stretching of pain endings. – some drugs work by both hypotheses. The second hypothesis has more to do with directly antagonizing the vasodilatory effects.
• So far sumatriptan is the first-line medication for migraines, but is contra indicated in coronary artery diseases. The mechanism of action is mainly debated as vasoconstrictor effects. Anti-inflammatory analgesics such as aspirin could also help. Beta blockers and some calcium channel blockers are good prophylactic medications to use for migraines by preventing vasodilation. Some anticonvulsants help as well. Verapamil also has modest efficacy as a prophylactic agent.