Inflammation: drugs

Question 1

First generation antihistamines

Answer 1

Mepyramine, Promethazine

Not very selective, actions in CNS cause drowsiness

Question 2

Second generation antihistamines

Answer 2

Terfenadine (prodrug, metabolised to its active form fexofenadine)
More selective, couldn’t cross BBB
Withdrawn due to cardiac toxicity

Question 3

Terfenadine toxicity

Answer 3

Metabolised to fexofenadine by 3A4 isoform of cytochrome P450
3A4 isoform may be inhibited by e.g ketoconazole, grapefruit juice
If not metabolized sufficiently, can affect heart via block of HERG channel (Kv11.1) -> torsade de pointes, hence long QT interval, potentially fatal arrythmia

Question 4

Third-generation antihistamines

Answer 4

Loratidine, Fexofenadine
Fewer CNS effects, not action on heart
Fexofanadine has a much lower affinity for Kv11.1 than Tetrafenadine

Question 5

Dimenhydrinate (Dramamine)

Answer 5

CNS-penetrant antihistamine used to treat motion sickness

Question 6

Prevention of mast cell degranulation

Answer 6

Salbutamol, salmeterol, sodium cromoglycate

Question 7

Salbutamol

Answer 7

B2 adrenergic agonist

Inhibit degranulation of mast cells
Used in asthma- cause direct bronchodilation

Question 8

Salmeterol

Answer 8

B2 adrenergic agonist
Longer acting than salmeterol

Inhibit degranulation of mast cells
Used in asthma- cause direct bronchodilation

Question 9

Sodium cromoglycate

Answer 9

Blocks mast cell Ca2+ channels and so inhibits degranulation (exocytosis from mast cells)

Question 10

Cimetidine (tagamet)

Answer 10

H2 selective receptor antagonist- reduces gastric acid secretion.
Used to treat gastric ulcers

Question 11

Ranitidine (Zantac)

Answer 11

H2 selective receptor antagonist- reduces gastric acid secretion.
Used to treat gastric ulcers

Question 12

Omeprazole

Answer 12

Proton pump inhibitor (reduces gastric acid secretion)

Question 13

Clarithromycin

Answer 13

Antibiotic used to treat helicobacter pylori

Treatment for peptic ulcers

Question 14

Metronidazole

Answer 14

Antibiotic used to treat helicobacter pylori

Treatment for peptic ulcers

Question 15

Ecallantide (Kalbitor)

Answer 15

Kallikrein inhibitor (mimics an antibody binding domain)

Kallikrein is a protease, cleaves high-molecular weight kininogen (blood) to bradykinin, or low-molecular weight kininogen (tissues) to kallidin.

Treatment of hereditary angioedema (rare acute inflammatory condition caused by low levels of C1-INH, characterised by episodes of severe, often painful swelling)

Question 16

Asprin

Answer 16

Non selective COX inhibitor
Anti-thrombotic at low doses
Irreversible. Donates acetyl group to a serine near the binding site of COX enzymes. Product is salicylate, a reversible competitive COX inhibitor, but [ ] probably not high enough to have much effect.

Side effects specific to asprin: salicylate poisoning, Reye’s syndrome, hypersensitivity reactions

Question 17

Ibuprofen

Answer 17

Reversible, non-selective COX inhibitor

Question 18

Paracetamol

Answer 18

Non-selective COX inhibitor. Little anti-inflammatory action

Question 19

Celecoxib

Answer 19

COX-2 selective inhibitor

Question 20

Rofecoxib

Answer 20

COX-2 selective inhibitor

Withdrawn because of increased incidence of MI

Question 21

Ondansetron

Answer 21

5-HT3 antagonist

Anti-emetic

Question 22

Metoclopramide

Answer 22

D2 antagonist

Anti-emetic

Question 23

Phenothiazines

Answer 23

D2 antagonists

Anti-emetics

Question 24

Scopolamine

Answer 24

Muscarinic antagonist

Anti-emetic

Question 25

Mepyramine

Answer 25

H1 antagonist

Anti-emetic

Question 26

Triptans e.g sumatriptan

Answer 26

Class of 5-HT1D antagonists
Used to control migrane. Remarkably effective in suppressing migrane- mechanism not known but implicates 5-HT in origin of migrane

Question 27

Ergotamine

Answer 27

Non-specific 5-HT1 agonist used to control migrane

Question 28

Preventative measures for migrane

Answer 28

Valproic acid
B-adrenoceptor blockers
Ca2+ channel blockers

Question 29

Treatment of peptic ulcers

Answer 29

Older treatments: antacids, cholinergic blockade, vagotomy.

Newer strategies (often combined):

• H2 selective antagonists e.g cimetidine, ranitidine
• PPIs e.g omaprazole
• Eradication of H.pylori e.g clarithromycin, metronidazole

Question 30

Side effects of NSAIDS

Pharmacological strategies to reduce gastrotoxic effects (8)

Answer 30

Nephropathy, prolonged gestation, GI damage, ulceration, bleeding, anaemia.

Pharmacological strategies to reduce gastrotoxic effects:

• Enteric coating: reduces topical damage
• NSAID prodrug: minimises level of action at gastric mucosa
• NSAID + NO: slow release of gastroprotective NO
• NSAID + misoprostol: PG substitute
• NSAID + PPI: prevents acid secretion
• NSAID + vitamin C: antioxidant effect
• Selective COX 2 inhibitor: COX 1 still active
• Inhibition of COX and 5-LOX: prevents leukotriene formation