Serotonin, angiotensin, prostaglandins, leukotrienes and their antagonists

Question 1

Explain the Serotonin (5-HT) Agonists.

Answer 1

1. 5-HT 1A ( Cerebral cortex/Raphe nucleus) seratoninergic agent for this receptors “BUSPIRONE” exerts a anxiolytic and anti-depressive effect, hence used for the treatment of general anxiety disorders. PK’s - oral administration, hepatic metabolism and urinary excretion. ADR,s are headache, dizziness and nausea.
2. 5-HT 1D (Cranial circulation) e.g “SUMARTRIPTAN” is responsible for vasoconstriction of the cerebral blood vessels, for the treatment of acute attacks of migraine. Pk’s - Samartiptan has high first pass metabolism ( Low BA and low DOA ) and has renal excretion.
3. 5-HT4 (Brain -learning/memory and in the GIT - stimulating peristalsis, aids gastric emptying). E.g: “METACLOPRAMIDE” which has dopamine antagonist function (D2 receptor blockage) and 5-HT4 agonist function. Pk’s- Oral,IM and IV administration, BBB/BPB distributions. Hepatic metabolism and urinary excretion. Used to treat, nausea, vomiting and delayed gastric emptying. D2 blockage leads to sedative effects and “extra-pyramidal effects (slurred speech, tremor, anxiety and paranoia).

Question 2

Explain the 5-HT antagonists.

Answer 2

These receptors are blocked through interaction with the following drugs:

1. 5-HT 2A receptors, substrate = “CYPROHEPTADINE” and atypical anti-psychotics “CLOZAPINE”, located in platelets, cerebral neurones and smooth muscle of vessels. Treatment of migraine and has anti-allergic effects. Pk’s - Oral absorption, BBB/BPB distribution, hepatic metabolism and urinary excretion. Treatment of schizophrenia (excessive serotonin levels).
2. 5-HT3, substrate = “ODANSETRON”, located in chemoreceptors trigger zone / vomiting centre, used as an anti-emetic in patients. Pk’s - oral administration, hepatic metabolism and urinary excretion.
3. Serotonin re uptake inhibitors e.g: SSRI’s such as Fluoxetine and Paroxentine, preventing serotonin re uptake into “pre-synaptic neurone after being released”, used as anti - depressant drugs. Pk’s - oral administration, BBB/BPB distribution, hepatic metabolism and urinary excretion.

§ Do not use SRI’s with other seratoninergic drugs, due to risk of developing “Serotonin Syndrome” (confusion, agitation, muscle twitching, diarrhoea).

Question 3

Explain the Prostaglandin antagonists?

Answer 3

Membrane phospholipids converted to arachidonic acid via “Phospholipase A2” and arachidonic acid converted to PG’s via COX enzyme.

1. COX inhibitors (NSAIDS)
   - NSAID Classification?
   - Phk: oral absorption, hepatic metabolism and urinary secretion.
   - AE’s : Fever and mild pain. The lack of COX means low PG, low protection of gastric mucosa, leading to ulcerations and bleeding. Other effects of COX inhibitors are: Anti-inflammatory, analgesic, anti-pyretic and inhibition of the platelet aggregation.
2. Phospholipase A2 inhibitors (Corticosteroids)
   - Anti-inflammatory, anti-allergic and immunosuppressive effects, used for anti-inflammatory therapy.
   - Phk: Oral absorption, hepatic metabolism and urinary excretion.
   - AE’s: Skin atrophy, reduced muscle mass, hyperglycaemia and hypertension.

Question 4

Explain Leukotriene modifiers?

Answer 4

Arachidonic acid to leukotrienes is via LOX enzyme.

1. Leukotriene receptor antagonists : MONTELUKAST, blockage of leukotriene receptor, inhibiting eicosanoid function.
2. Leukotriene inhibitors: “ZILEUTON” (reduce the production of the leukotrienes from the LOX unlike the antagonists).

Oral absorption, BBB-PBP distribution, hepatic metabolism and urinary excretion. Used to control the symptoms of asthma by stimulating broncho-dilation and exerting anti-inflammatory effects.

Question 5

Explain Angiotensin antagonists.

Answer 5

1. ACE inhibitors (Captopril and Enalapril).
   - Oral administration, BBB-BPB distribution, hepatic metabolism and urinary excretion.
   - Hypertension treatment
   - AE’s: Dry cough, angio-oedema, loss of taste, hyperkalemia and hypotension.
2. Angiotensin 2 receptor blockers : “LOSARTAN” , hypertension treatment.
   - AE’s: hyperkalaemia, hypotension and angio-oedema
3. Renin inhibitor : “Aliskiren” , treatment of hypertension with same adverse effects as losartan.