1. There is little doubt that the pathology of migraine depends strongly on a vascular component.  Both vasoconstrictors and vasodilators are effective in some cases of migraine.  Furthermore, even though vasoconstrictors are effective in migraines, it does not mean that drugs that cause vasodilation are necessarily the culprits which precipitate migraines.  It appears that migraine comprises far-reaching changes in vascular functions, which are unpredictable, especially if we take into consideration that anti-inflammatory drugs which have no direct vasoactive action, are also effective.  Read the part on the treatment of migraine (Katz).  Prepare a rationalisation of the pathology of migraine as well as current treatments and how they work and submit in as a blog summary.  

The involvement of trigeminal nerve distribution to intracranial arteries, with release of powerful vasodilators (CGRP) that cause vasodilation and oedema, that activating pain nerve endings.

Treatment :

Sumatriptan - activate 5-HT1B receptors, vasoconstriction of cranial nerves

Prophylaxis - flunarazine is a calcium ion blocker

                     propanalol is a beta blocker

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

Calcium increases intracellularly in the endothelial cells. This will lead to the formation of NO. The NO moves to the vascular smooth muscle and causes the muscle to relax(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.

Constitutive enzymes are produced all the time, where inducible enzymes are only produced when the correct subsrate is present.

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

If endotoxins are present, iNOS will form in the smooth muscle. This will cause high levels of NO to be produced. This will cause low blood pressure and can lead to septic shock.

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

No ( nitric oxide)

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

NOS inhibitors. The interact with L-arginine that makes NO. Lower levels of NO will be produced. 

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

An overproduction of NO induces inflammatory. 

Disadvantage - tissue damage and asma

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

alzheimeras disease

parkinsons disease

stroke

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

Paracetamol - COX-1 and COX-2 inhibitor(weak)

                       - no anti-inflammatory effects

Aspirin - COX-1 and COX-2 inhibitor

             - has anti-inflammatory effects

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

- antipyretic(reduce fever)

-analgesic(for pain)

Used for headache, toothache, mild to moderate pain with no inflammation

Drug of choice for pregnancy, patients with asma, gout and patients that bleed easily(peptic ulcers)

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

An allergic reaction that causes a rash and swelling

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

Dose : 10-15 g

Signs/symptoms : 

1-2 days after dose - nausea and vomiting , abdominal pain, decreased appetite and feeling fatigued

After the 1-2 days - right subcostal pain, jaundice, tar liver and can develop renal insufficiency, liver necrosis and death.

Treatment - give -SH group supplement immediately

                    - N-acetylcysteine given through IV within 8-12 h after overdose

                    - within 1 hour - make patient vomit, stomache flushing

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

A genetic metabolic disease that results in induced secretion in various organs, such as excess mucus in alveoli. Mucus is thick and sticky and cannot be cleared by body. Regular bacterial infections occur.

Dornase alfa inhalations hydrolyze the proteins in bronchial mucus to improve fluidity.

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

Immature lungs of a newborn baby that causes breathing disorders. Usually occur in premature babies. Surfactant needed for gas exchange has not formed yet, leads to lungs falling flat. 

Treatment - oxygen therapy

                    - corticosteroids such as betamethasone given to mother before birth helps surfactant being formed

                    - ventilation keeps positive pressure in lungs                        

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

It ensures that oxygen levels of the baby are in the correct index. To high levels can cause retinal failure and blindness. Therefore intensive monitoring is required.

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

The respiratory center in the brain has not developed fully yet and cannot stimulate continuous breathing.

Treatments - oxygen therapy

                      - methylxanthines used are theophylline and caffeine. They are lipophilic, cross the brain barrier, and reach the CNS. 

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

rhinitis - caused by colds and flu and are presented as inflammation of the nasal mucosa

              - can also be due to allergens, physiological due to heat/smoke, or sinusitis.

rhinorrhoea - caused by cold, allergen, chemical or drug damage, cold air, physical damage

                      - presented as a runny nose

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

α1- agonists such as phenylephrine 

antihistamine such as chlorpheniramine

corticosteroids such as prednisone

mast cell stabilisers such as ketotifen

mucolytic such as mesna 

antibiotic like neomycin

divers drugs like steam/eucalyptus oil

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

Mechanism of action - alpha adrenergic receptors on nasal cavity stimulated, vasoconstriction of mucosal blood vessels. Decrease in nasal mucosa.

Duration of action - long and short acting(nasal spray)

                                 - short acting preferred, long acting can effect the heart and CNS(concentration decreases).

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

Develops when topical decongestants such as nasal spray or gels(oxymetazoline or xylometazoline) are used for longer than a few days or as prescribed. Tolerance builds up, and worsens symptoms. 

Treatment - progressively lower use of drug, but do not stop suddenly, as it can worsen symptoms

                    - nasal corticosteroids such as mometasone 

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 antihistamine - lead to sedation, lipophilic, cross blood brain barrier(lowered concentration)

                                                      - muscarinic blocker( decreased mucus secretion)

Second generation antihistamine - no muscarinic blocking effect, only used for allergic rhinitis 

                                                            - not lipophilic, do not cross blood brain barrier, no sedation

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

Corticosteroids - nasal spray

                            - used in allergic rhinitis and to reverse rhinitis medicamentosa

Anti-allergic drugs - nasal spray

                                  - allergic rhinitis /(stabilize mast cells)

Mesna - mucolytic drug administered through steam inhalation

             - liquify tough mucus 

Salt solution - nasal drops

                       - hydrate inflamed and dry mucus membranes

ACE(angiotensin converting enzyme) inhibitors such as omeprazole and leflunomide can cause cough.

1. Give your own definition of COPD.

Chronic obstructive pulmonary disease(COPD) is a disease where the airway is constricted(bronchial constriction) or there is mucus blocking the airway. This makes it difficult to breathe. Common conditions are emphysema, chronic bronchitis and asthma.

2. Briefly describe the proposed aetiology and pathophysiology of chronic bronchitis and emphysema.

Chronic bronchitis is an inflammatory disease that flares up. It happens due to increased mucus production and decreased mucus clearance. Irritants that are inhaled can also cause inflammation. Infections in the airway occur often. 

Emphysema is where the alveoli's are damaged due to smoking and other irritants. Old air cannot get out and new air cannot get in. It is difficult to breath. 

3. Which types of therapy are included in the treatment of a COPD patient?

- stop smoking

- rehydration and steam can dilute mucus

- bronchodilators can open airways

- hypoxia(regular O2 inhalation)

- first line drugs used are anticholinergic drugs such as tiotropium or ipratropium that will inhibit bronchoconstriction. 

4. Why is ipratropium more effective in the treatment of chronic bronchitis than in the treatment of bronchial asthma?

Ipratropium - short acting anticholinergic drug

                       - bronchial smooth muscles relax, lead to bronchodilation

                       - decrease mucus secretion(chronic bronchitis)

B2-agonist are first line drugs for asthma, and anticholinergic drugs are only used when a tolerance against b2-agonists have developed.

5. In which way do the skeletal muscle effects of theophylline have advantages in the treatment of COPD?

Theophylline increases the skeletal muscle strength of the diaphragm. Ventilation is increased and therefore a higher O2 level is achieved. 

6.  What is the role of oxygen therapy in COPD?

Oxygen therapy is done when a patient cannot breath due to a constructive airway. This will lead to lack of enough oxygen. Oxygen therapy is done to give the patient the necessary oxygen needed to survive.

1. What are the therapeutic effects of theophylline in the treatment of bronchial asthma?

- prophylactic effects

- COPD use

- reduces shortness of breath, chest tightness and low oxygen in COPD patients

- relaxes and opens airways, easier to breath

2. What are the primary mechanisms according to which the therapeutic effects are evoked? What is the mechanistic connection with b₂-agonists and antimuscarinic drugs? How would you describe the interaction with the b₂-agonists molecular-pharmacologically? 

Mechanisms - smooth muscle relaxation

                        - suppression of response of airway to stimuli 

Mechanism connection - b₂-agonists acts as functional antagonist of all mediators of bronchial constriction, and antimuscarinic drugs are competing antagonists.

 b₂-agonists - relax airway smooth muscles and open airways

                      - stimulate beta-2-adrenergic receptors

                      - increases cyclic AMP

                      - antagonizes mechanism of bronchoconstriction

3.  On which other systems in the body do the methylxanthines have an effect?  Where do you see the potential for undesirable side-effects and possibly also for other therapeutic applications of these side-effects?  Place special emphasis on the central and skeletal muscle effects.

- Renal - glomerular filtration rate increases, frequent urination

- Central nervous system - insomnia(sleeplessness)

                                              - very alert

                                              -therapeutic : can give energy when feeling tired

-Gastrointestinal tract - increased secretion of digestive enzymes

- Skeletal muscles - diaphragm skeletal muscles contract stronger 

 COPD patients benefit due to increased ventilation(higher O2 levels).                                             

4. What can you say about serious toxicities and the therapeutic index of theophylline?  How can the plasma levels of theophylline be influenced by pharmacokinetic drug interactions?  With which drugs can it be clinically important and why?

Theophylline has small therapeutic index. Do not exceed 20 µg/ml, can lead to nausea, vomiting, headache, insomnia. Serious toxicities exceed 40 µg/ml, which leads to heart dysrhythmia and convulsions.

Drugs such as erythromycin, propranolol, isoproterenol, cimetidine and oral contraceptives can increase theophylline levels and should therefore be administered in a smaller dose if taken with these named medications.

5. How is theophylline administered?  What are the advantages of the slow-release forms? 

-IV

-orally

-inhalation

- slow release forms will supress symptoms of bronchial asthma for a longer period of time

6. You have a patient who uses theophylline for the treatment of chronic asthma.  Your patient, however, develops a cold leading to a worsening of asthma.  After a week your patient develops a secondary bacterial infection and the doctor prescribes a penicillin antibiotic.  You are an alert pharmacist and quickly detect that your patient is allergic to penicillin.  You phone the doctor who suggests that you must rather give erythromycin antibiotic.  Do you think it is a good idea?  Assume your patient has developed a genitor-urinary tract infection, do you think it is a good idea to use ciprofloxacin?  And if she has a problem with heartburn, are there drugs that you should be careful to recommend?  Make use of your SAMF in considering the case.

Erythromycin and Ciprofloxacin inhibits liver enzymes. These enzymes are used to metabolize theophylline. Theophylline levels will rise in the body and lead to toxic effects.