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

Migraine pathology

Migraine is a primary brain disorder most likely involving an ion channel in the aminergic brain stem nuclei (←), a form of neurovascular headache in which neural events result in dilation of blood vessels aggravating the pain and resulting in further nerve activation.

Migraine typically recurs over a period lasting 4 to 72 hours and is often incapacitating. The primary type is migraine without aura (formerly called common migraine). This condition is commonly unilateral (affecting one side of the head), with severe throbbing or pulsating headache and nausea, vomiting, and sensitivity to light & sound.

Treatment

•  Anticonvulsants valproic acid and topiramate.
• Flunarizine a calcium channel blocker which reduces the severity of the acute attack and to prevent recurrences.
• Verapamil which is considered to have modest efficacy as prophylaxis against migraine

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

Increased levels of angiotensinogen are associated with a condition of essential hypertension.

These levels are increased by glucocorticoids, oestrogens, thyroid hormone, and angiotensin II.

Therefore, this explains the increase

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

ACE inhibitors may cause a dry cough and angioedema due to the increased levels of bradykinin, because angiotensinogen receptor blockers do not influence bradykinin there is little to no dry cough as a side effect

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

It Prevents the conversion of Angiotensin I to angiotensin II, thus inhibiting the release of aldosterone. Therefore, the action of ACE inhibitors to inhibit bradykinin and other substances contributes to lowering the 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?

The drugs act at AT1 receptors and when ANG II is increased, they act on the AT2 receptors.

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

Kinins cause vasodilation on arteries due to the direct inhibitory effect of kinins on arteriolar smooth muscle or it is mediated by the release of nitric oxide or vasodilator prostaglandins such as PGE2 and PGI2. Kinins cause the veins to contract due to direct stimulation of venous smooth muscle or from the release of vasoconstriction prostaglandins PGF 2 alpha. Autacoids such as bradykinin play a role as bradykinin is a potent vasodilator.

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

Type b2 receptor

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

Natriuretic peptides lead to the following physiological occurrences: Increased renin production, increased ANG2, vasodilation and natriuresis

• 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 zinc-dependent metalloprotease that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin.

The rationale of inhibiting them is to ensure an increase in the systemic concentration of the Natriuretic peptides and so ensure that their physiological effects are effective

• Give examples of endothelium-derived vasodilators and vasoconstrictors. 

Vas0dilator nitric oxide and PGI2

Vasoconstrictor ET1 and receptor subtypes ETA and ETB

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

Cystic fibrosis is a genetic metabolic disease (↓ DNase 1) that results in reduced secretions in various organs

 • Worst symptoms visible in airways

• Mucus is thick and sticky and leads to recurrent bacterial infections

• Body does not have the ability to clear mucus

Dornase alfa- Hydrolyze proteins in bronchial mucus to improve fluidity.

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

Also known as hyalin membrane disease • Occurs in premature babies • Surfactants that cover airways and are essential for gas exchange are only formed shortly before birth • Lungs can therefore fall flat (atelectasis) → death • Intensive monitoring of respiratory and circulatory status essential

Treatment-Oxygen to ensure oxygenation

 • Ventilation used for positive pressure

• Drug: exogenous surfactant: beractant, poractant alfa

• Corticosteroids such as betamethasone - are also given prophylactically to mother before labour to initiate baby's surfactant production

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

Oxygen ensures oxygenation , dangers is that Increased oxygen over long term leads to retinal damage and blindness

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

• In newborns and premature babies

 • Respiratory centre in brain not yet fully developed to stimulate continuous breathing • Apnea with bradycardia lasts longer than 15 seconds and occurs repeatedly

• May cause hypoxia and neural damage

Theophylline and caffeine

• general causes of rhinorrhea and rhinitis

-commo cold

-sinusitis

-allergen exposure 

- physiological reaction to stimuli such as heat , smoke , cold or other irritants

• groups that can be use for treatment of rhinorrrhoea ? name eexamples of each group

anti-microbial- mupirocin

alpha 1 agonist ephedrine

antihistamine- diphenhydramine

corticosteroid- betamethasone

anti-allergic - sodium cromoglycate 

mycolytics - mesna

diverse drugs- saline

• how do decongestant differ in terms of moa and duration of action . how they administered

moa: sympathomimetic effect , alpha agonist , cause vasoconstriction of mucosal blood vessel and lead to a decrease in oedema of the nasal mucosa

duration - last up to 12 hours , do not administer after 4 pm , do not use for more than 5-7 days

they are administered topically by metered dose spray

• what is rhinitis medimentosa? and how is it treated ?

is condition that develops due to the chronic treatment by decongestant , where it damages the mucosal membrane , causing a permanent  vasoconstriction of poor local blood supply that lead to permanent swelling and inflammation of the nasal mucosa

treated by ceasing the usage of decongestant , and use corticosteroid therapy for the reversal of privinism.

• how does the first and second generation of histamine differ with mechanism and advantage of the second 

first generation block the muscarinic receptor, anti- muscarinic drugs reduces the upper and lower secretion of airways ,thus they are used in cold preparation to clear cold rhinorrhea

second generation do not block the muscarinic drugs  used in treatment of allergic rhinitis

histamine takes no pat but the bradykinin does

advantage- have CNS effects ,low cases of sedation

• -corticosteroid are acceptable for  allergic rhinitis
• -anti-allergic acceptable when they are being used prophylactically 
• mesna dissolving sticky and thick mucus 
• normal saline acceptable when humidifying dry and swollen mucus

• definition of copd 

a group of lung disease that block airflow and make it difficult to breath

• pathophysiology of chronic bronchitis and empysema

- chronic bronchitis

Non -specific obstructive airway disease, characterized by: •  Mucus secretion •  mucosal clearance • Frequent bacterial respiratory infections • Structural changes in bronchial walls • Chronic cough due to sticky mucus

- empysema

Often develops due to smoking and irritants • Emphysema is Irreversible dilation of respiratory bronchioles and alveoli due to structural damage • Air is trapped in lungs - difficult exhalation Capillary blood vessels - impede gas exchange

• therapy included in treatment of copd patient

smoking ceassation, bronchodilators , corticosteroid , methylxanthine ,oxygen , surgery

• why is ipratropium more effective in the treatment of chronic bronchitis than in the treatment of bronchial asthma.

ipratropium has a slight anti-inflammatory effects( it also had antimuscarinic effects hence it will have relaxation of muscles  and chronic bronchitis is inflammation on the lining of the bronchial tubes.

• in which do the skeletal muscle effects on the theophylline have an advantage on COPD ?

increases the contraction of the diaphragm in skeletal muscles ,which improves ventilation capacity in copd patients

• oxygen is used to provide oxygenation in patient who could not properly breath on their own

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

It means endothelium controls vascular tone in  a paracrine fashion , by secreting diffusible soluble mediators able to act on physically contiguous cells.

• 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  means continuous transcription of gene , and constitutive enzymes are enzymes that are produced independently and are regarded as house keeping.

Inducible means that the presence of an inducer causes an increase in gene expression enzymes are adaptive enzymes used for breaking down in the cell.

• 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. thus hyperproduction of NO by the inducible form of NO synthase (iNOS) may contribute to the hypotension, cardio-depression and vascular hypo-reactivity in septic shock.

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

Nitric oxide

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

Arginase is an enzyme in the urea cycle that hydrolyses L-Arginine to urea. It suppresses nitric oxide production through various mechanism.

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

NO is considered as a pro-inflammatory mediator that induces inflammation due to over production in abnormal situations.

Advantage- it play a role in immune protection , if there are invasive foreign pathogens during inflammatory response , cells respond by production NO to boost the immune.

Disadvantage- affects apoptosis and cell death.

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

Major depression , schizophrenia ,bipolar

• What is the mechanism of action of colchicine in the treatment of gouty arthritis. It is a selective inhibitor of micro-tubules and spindle formation macrophages and leukocytes ( thus inhibiting mitosis) Also inhibits chemotaxis .Decrease leukocytes metabolism , thus reducing lactic acid formation and increasing PH
• 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

Indication- acute gout arthritis

Side effects- gastric discomfort , diarrhea , nausea , abdominal pain , gastric bleeding at high dose, liver damage , kidney disease , bone marrow suppression , peripheral neuritis , alopecia

Dose- 0.5-1mg immediately , followed by 0.5 mg every 6 hours until the pain relief or gastric discomfort is reached . max 2.5 mg in first 24 hours

No more than 6 mg over 4 day

Course may not be repeated within 3 day.

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

Prednisone ,triamcinolone , methylprednisolone

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

Probenecid belongs to the uricosuric   , that lowers  uric acid in your body by assisting  the kidneys in excreting excess uric acid.

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

It reduces the conversion of xanthine to uric acid , thus reducing the production of uric acid

Thus it increases xanthine and hypoxanthine

Indication – chronic gout

Precautions – avoid in acute gout attack

Interactions- has no known severe interactions with other drugs

2.7 blog exercise b

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

Before there is vasodilation which induces migraine and it is followed by vasoconstriction.

• What is the role of serotonin in migraine headaches?

Serotonin is a chemical necessary for communication between nerve cells . it can cause narrowing of blood vessels throughout the body , thus when serotonin levels migraine result.

• How is ergotamine used during a migraine attack?

Is only effective if taken with first signs of migraine , can cause direct vasoconstriction especially for intracranial arteries.

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

Nausea & vomiting , hallucination and confusion, diarrhea , gangrene , retroperitoneal fibrosis , tachycardia

Contraindications

Coronary , cerebral & peripheral diseases , uncontrolled hypertension , hepatic and renal impairment and pregnancy.

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

NSAIDs , aspirin , cyclizine  , paracetamol

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

Propranolol, clonidine, flunarizine , topiramate ,pizotifen

Side effects : bradycardia , drowsiness , git disturbances , sexual dysfunction and nightmares.

Precaution – do not use if you have asthma , heart failure , pregnancy , depression and type 1 diabetes.

• 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 (SSRI) that is approved by the Food and Drug Administration (FDA) for the treatment of obsessive-compulsive disorder and is used for other conditions, including depression, but Fluvoxamine is not FDA-approved for the treatment of any infection.

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.¹ In an in vitro study of human endothelial cells and macrophages, fluvoxamine reduced the expression of inflammatory genes. but there not been sufficient proof on whether the anti-inflammatory effect on nonclinical studies same applies to human. therefore there has not been any proof that indeed fluvoxamine may help in the treatment of covid-19

(National institute of health).2021.http//www.covid19treatmentguidelines.nih.gov/therapies/immunodulators/fluvoxamine/ date of access:23 oct 2021

• mechanism of paracetamol and how differs from aspirin

paracetamol is a weak cox 1 and cox 2 inhibitor peripheral, has no anti-inflammatory effect, blocks cox 3 CNS activating declining serotonergic analgesic pathway. differs from aspirin because aspirin has an inflammatory effect and it does have an effect on cox 3

• indication of paracetamol and condition which it may be used for mild pain and fever

pain , fever , as an antipyretic( temperature regulation, peptic ulcer, hemophilia and asthma and it can be used on mild pain and fever as choice if they are of somatic origin

• side effects of paracetamol

-low fever , nausea, dark urine , jaundice and loss of  appetite

• acute paracetamol toxicity, doses , symptoms and treatment

paracetamol is only safe in low doses but in high doses it becomes very toxic, though at therapeutic dosage it is well tolerated but it must be adjusted in alcoholic people , people with liver and kidney diseases and in people with anemia as it may cause more damage

paracetamol toxicity may lead skin rash and urticaria

within 1-2 day of paracetamol poisoning the patient may experience nausea , vomiting , abdominal pain decreased appetite ,tired and powerless and then after the 1-2 days they maybe start experiencing right subcostal pain , tar liver , jaundice renal insufficiency and liver necrosis or death

treatment 

immediate supplementation  of SH-groups to supplement glutathione in liver and prevent liver cell necrosis 

N-acetylcysteine (parrolex) administered within 8-12 hours , Initial  dose 150mg/kg in 200 ml 5% glucose over 15 minutes , thereafter 50 mg/kg in 500 ml 5% glucose over 4 hours , thereafter 100mg/kg in 1000 ml 5% glucose over 16 hours 

oral treatment: acetylcysteine 140mg/kg or carboscistein 150 mg/kg