Name of Blog: Blog #3.5

Answer the following:

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

Cystic fibrosis is a genetic metabolic disease that causes decreased secretions in certain organs. The most problematic area is in the airways, the thick mucus is an ideal environment for bacterial infections as the body is unable to clear the mucus effectively. Manifestation in the lungs causes the neutrophils upon disintegration to deposit DNA in mucus in the airways- increasing the mucus build-up. This cycle is then repeated with every infection. Dorsna-alfa is inhaled as therapeutic treatment. This hydrolyses extracellular DNA from the neutrophils in the bronchial mucus, increasing its fluidity. This is a highly expensive treatment and is usually used in combination with physiotherapy.

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

NRDS is also known as Hyaline membrane disease occurs in premature babies. A surface agent (surfactant that covers the airway and is vital for gaseous exchange) is produced right before the baby is born and can lead to lung collapse and death. General treatment strategies include close up monitoring of the respiratory and circulatory systems. Oxygenation and continuous positive airway pressure are administered through a ventilator which assists in keeping the alveoli dilated and preventing lung collapse. Receiving oxygen for extended periods of time can present toxic effects such as hypoxia, reduced gaseous exchange and can lead to retinal damage and blindness in neonates.

Drugs that can be administered include corticosteroids and exogenous surfactants.

Exogenous surfactants can be administered exogenously at room temperature or during acute respiratory distress to help stimulate the production of surfactant in the neonate. Examples of exogenous surfactants include beractant and colfosceril palmitate. Corticosteroids can be administered to help increase endogenous surfactants. Betamethazone can be administered to the mother before labour to initiate the endogenous surfactant production in the neonate. 

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

Oxygen therapy helps the neonate receive the oxygen their body requires. Increased oxygen inhalation over extensive periods of time can however lead to toxic effects such as hypoxia, decrease gaseous exchange in the airways and, especially in neonates, lead to retinal damage and blindness. 

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

Neonatal apnoea occurs in newborns and premature babies where their respiratory centre in the brain is not fully developed yet to simulate continuous breathing. This may lead to hypoxia and neural damage. Methylxanthines such as caffeine and theophylline can be used to stimulate the CNS.

Name of Blog: Blog #3.4

Answer the following:

1. What are the general causes of rhinitis and rhinorrhoea?

Rhinitis and Rhinorrhoea are generally caused by colds, allergy, drug or chemical or physical damage. Rhinitis can be subdivided into purulent rhinitis, allergic and non-allergic rhinitis.

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

Mucolytics- acetylcysteine and bromhexine, mesna.

Anti-infective-Neomycin and Mupirocin

Corticosteroids- Prednisone, Betamethasone, budesonide  

Anti-allergic- Sodium cromoglycate and nedocromil Sodium

Diverse- Volatile oils and Menthol, saline.

Soothers- Honey and liquorice

Decongestants (alpha- receptors)- Phenylephrine and ephedrine.

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

There are systemic decongestants administered orally and local decongestants administered by a spray. Decongestants are sympathomimetic a1 receptors that cause vasoconstriction in the nasal cavity which reduces oedema. Systemic decongestants are rarely used (Ephedrine) as they are misused, cause CNS(Anxiety, insomnia and sleeplessness.) effects and have Cardiac side effects. Local decongestants such as oxymetazoline and xylometazoline have fewer side effects but can only be used for about three days else rebound decongestion occurs.

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

Rhinitis medicamentosa is rhinitis induced by the overuse of decongestants. It can be prevented by not using decongestants for more than three days. Possible treatments include stopping treatment and administering Saline (Via steam inhalation)

5. 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 are used to treat rhinorrhoea in patients suffering from a cold, they block muscarinic receptors which reduce secretions in the airway. They are however not commonly used due to their sedative effects and reducing ability to concentrate.

Second-generation antihistamines do not block muscarinic receptors but are used in the treatment of allergic rhinitis. These drugs are not useful in the treatment of colds.

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

These drugs can be used when a patient is suffering from rhinitis. Corticosteroids are administered orally or via nasal spray, anti-allergic drugs (sodium cromoglycate) are administered via nasal spray. Mesna is available as a spray for thick mucus. Normal salt solutions can be used for a nasal rinse.

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

Strong vasodilators cause vasodilation and oedema, which activate pain nerve endings. This pain can be described as one’s head feeling as though it is about to explode.

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

5-HT or serotonin receptors, agonists constrict the arteries which then inhibits trigeminal nerve transmission and vasoactive peptide release.

3. How is ergotamine used during a migraine attack?

Ergotamine is a partial 5-HT1 agonist which causes vasoconstriction in the intracranial arteries and inhibits trigeminal nerve transmission.

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

Side effects include nausea, vomiting, diarrhoea, hallucinations, gangrene strong vasoconstriction, tachycardia and rebound headache. Contra-indications include cardiovascular disease, hypertension, patients suffering from liver and kidney impairment, pregnancy, and psychosis.

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

Sumatriptan, Zolmitriptan, Almotriptan, Eletriptan, Naratriptan- These drugs are 5-HT1B/1D/1F agonists. They constrict the large arteries, inhibits trigeminal nerve transmission and vasoactive peptide release.

Metoclopramide-Anti-emetic, D2 antagonist at the chemoreceptor trigger zone in CNS

Cyclizine-Anti-emetic, First-generation ant-histamine, competitive antagonist at H1, muscarinic, alpha and 5-Ht receptors.

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

Beta-blockers and alpha 2 agonists can be used as migraine prophylaxis. Propranolol(B-blocker) helps to stop a migraine but should not be taken during a migraine. Clonidine (alpha-2 agonist) causes vasodilation before initial vasoconstriction, but caution should be taken as it could induce a migraine attack. Calcium channel blocker-drugs could also be used such as Verapamil, Flunarizine (could prevent often attacks of migraines, Blocks H1) and Diltiazem. These drugs cause vasodilation after initial vasoconstriction. Side effects when taking Flunarizine include weight gain, depression, and fatigue.

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

When Colchicine is administered it binds to the intracellular protein tubulin, inhibiting polymerization into microtubules which then prevents leukocyte migration and phagocytosis. By preventing the migration of leukocytes to the side of inflammation, ingestion of urate crystals and release if more inflammatory mediators will not occur. Colchicine also inhibits the formation of leukotriene B4 and IL-1β

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.

Colchicine is used to treat gout and in between gout attacks.

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

Other drugs include NSAIDs such as Indomethacin, Diclofenac, Piroxicam.

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

Probenecid is used for chronic gout and falls under uricosuric drugs. These drugs compete with uric acid for reabsorption in the proximal tubule located in the kidney.

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

Allopurinol inhibits Xanthine oxidase which then prevents Xanthine from forming uric acid in the body. This drug is used for chronic gout. Allopurinol can induce acute gout if not taken with NSAIDs. A caution to be taken is to be aware of the increased effects of cyclophosphamide which inhibits the metabolism of probenecid and oral anticoagulants which increases iron concentration.

Colchicine or NSAIDs are given initially with Allopurinol to help prevent gouty arthritis episodes.

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

Paracetamol is a weak COX-1 and COX-2 inhibitor. It contains analgesic and antipyretic effects. Unlike aspirin it has no anti-inflammatory effects, nor does it affect platelet aggregation.

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

Paracetamol is given for light to moderate pain. It would be the drug of choice for patients who are pregnant, have asthma, gout, suffer from peptic ulcers and haemophiliac patients.

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

General side effects include skin rash, urticaria.

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.

Paracetamol toxicity

Paracetamol toxicity occurs when live catalysing conjugation is saturated, that is when toxic NAPQI is formed. The glutathione “pathway” is diminished, causing an excess/ accumulation in NAPQI which then leads to hepatotoxicity.  Unfortunately, paracetamol toxicity is a common suicide method.

Dose

Toxic doses include anywhere between 10-15g of acetaminophen.

Signs and symptoms

This includes nausea, vomiting, abdominal pain, fatigue, weakness, renal impairment, and hepatotoxicity that occurs at a later stage.

Treatment

Treatment for acetaminophen toxicity includes therapy that contains NAC, which helps restore glutathione which conjugates with NAPQI, leading to non-toxic effects. Within 1 hour of the overdose, one can induce vomiting, gastric lavage or use activated charcoal.

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

This means that the endothelium cells in vascular tissue relax (dilate) when exposed to vasorelaxants through the release of endothelial-derived relaxing factor (EDRF). This factor induces relaxation of the vascular muscle. Endothelium-dependant vasodilators include acetylcholine and bradykinin. These vasodilators increase the calcium concentration inside the cells which induces Nitric oxide synthesis. The NO then travels to the vascular smooth muscle leading causing vasorelaxation.

2. 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 inducible enzyme are enzymes that are only active/present when needed and is used to break down molecules whereas constitutive enzymes which are continually being produced

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

Sepsis is inflammation caused by infectivity. The increased synthesis of NO contributes to more intense hypertension, shock and rarely possible death. Hypertension can be reversed via NO synthesis inhibitors such as sGC inhibitor methylene blue.

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

Autacoids act as local hormones in the body. When NO diffuses into the smooth muscle it activated the synthesis of guanylyl cyclase cGMP. This product activated protein kinase G decreasing the inward flow of calcium into the cell. With calcium influx being reduced the muscle will cease to contract.

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

Regarding the damage caused by NO through chronic and acute inflammation, iNOS inhibitors can serve as a form of protection.

NOS inhibitors can also be used in therapy to decrease neuronal damage.

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

NO can stimulate the synthesis of inflammatory prostaglandins through the activation of COX-2, this then produces the desired vasodilation effect. NO has its advantages by contributing to increased vascular permeability and disadvantages where the prolonged effects of NO (inflammation) can cause tissue damage.

7. In which possible neurological and psychiatric diseases is NO involved? 

NO acts as an important neurotransmitter in the CNS. NO is synthesised at the post-synaptic cleft. When too much NO is synthesised it can cause excitotoxic neuronal death in neurological diseases such as amyotrophic lateral sclerosis a d Parkinson’s disease.

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

Angiotensinogen levels increase when low blood pressure is detected. High levels of angiotensinogen lead to hypertension.

• 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 ACE allow a surplus of bradykinin in the body which is a potent vasodilator and can accumulate in the respiratory tract causing dry cough from the irritation (CI in patients with asthma). Angiotensin receptor blockers still allow the activity of ACE and so bradykinin can still be broken down into inactive metabolites by this enzyme, preventing any unnecessary side effects cause by the vasodilation.

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

ACE inhibitors such as Captopril, Enalapril and benazepril inhibit the conversion of angiotensin 1 to angiotensin 2. ACE also cannot break down bradykinin into inactive metabolites and so the bradykinin causes major vasodilation.

• 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 ii receptors. These drugs inhibit AT receptors at the heart, blood vessels kidneys and brain, decrease aldosterone release and thus the RAAS system.

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

Kinins cause vasodilatory effects.

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

B2 receptors

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

Natriuretic peptides cause vasodilation and so reduces blood pressure. A high concentration of ANP and BNP allows for the diagnosis of 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 ANP and BNP, a drug that inhibits this is sacubitril. By inhibiting its action the increased amount of ANP and BNP allows the increase of glomerular filtration and so an increase in sodium excretion. This causes a decrease in intervascular blood volume and so a decrease in blood pressure.

• Give examples of endothelium-derived vasodilators and vasoconstrictors. 

Bosentan.

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

Aspirin is a NSAIDs that inhibit the synthesis of cyclooxygenase. The arachidonic will still synthesis Cyclo-oxygenase which leads to an increase in the synthesis leukotrienes.LT are potent vasoconstrictors that cause bronchospasm. Bronchospasm is contraindicated in patients with asthma.

2. 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 needs to be released from membrane phospholipids in order to start the Eicosanoid process. AA is released by three different phospholipase classes.

First is Cytosolic PLA2 (phospholipase A2)

Secretory PLA2 (Calcium dependant)

Calcium independent PLA2 (Where chemical and physical stimuli activate the calcium translocation of PLA2 to plasma membrane, this then allows the release of Arachidonic acid and so the start of the Eicosanoid synthesis.

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

Leukotrienes and Thromboxane.

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

Cyclo-oxygenase plays a direct part in the inflammation process specifically as it synthesises PGI2, TXA and PG.

5. Give an example of the following:

A drug that inhibits each of the following enzymes:

phospholipase A; Hydrocortisone, Dexamethasone, Prednisolone.

cyclooxygenase; Aspirin, ibuprofen

lipoxygenase, Zileuton

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

Montelukast, Zafirlukast

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

Thromboxane promotes platelet synthesis whereas prostacyclin inhibits platelet aggregation. As soon as a Cyclo-oxygenase inhibitor is used no platelet aggregation will occur.

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

Alprostadil is PGE1, which induces vasodilation and inhibits platelet aggregation.

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

Misoprostol is a PGE1 eicosanoid that helps protect the gastric mucosa preventing the formation of sores within the stomach lining i.e., gastric ulcers.

• Prostaglandin is possible of value in asthma.  Which PG_E2- or PGF_2A-analogues will be effective in such a case?

PGE2 would be of better value because PGF2 is a potent bronchoconstrictor.

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

Latanoprost increase the outflow of aqueous humor.

5-HT 1D/1B agonists such as triptans are primarily used for migraines. Migraines can include nausea, vomiting, visual scotomas and even sometimes hemianopsia and speech abnormalities. The common excruciating throbbing in the head can last up to two days. Migraines include trigeminal nerve distribution towards the intra-canal arteries, to which these nerves release peptide neurotransmitters such as Calcitonin gene-related peptides, causing major vasodilator. Drug classes such as Triptans, ergot alkaloids and antidepressants. These drugs activate the 5-HT 1D/1B receptors which inhibit the release of peptides. Other drugs that contain antiseizure agents can decrease the rapid release of neurotransmitters. Analgesicts such as asprine and ibuprofen can help to eliviate the pain aswell. Direct 5-HT agonists can cause vasoconstriction, therefore prevent the vasodilation of the arteries and help subside the stretching of the nerve pain endings.

Other drugs include Propanolol and amitriptyline. Anticonvulsants drugs such as valproic acid and topiramate help alleviate migraines, as well as Verapamil and calcium channel blockers-Flunarizine.