301 Chemistry

Question 1

Examples of immunological diseases

Answer 1

1. Rheumatoid arthritis
2. Multiple sclerosis
3. Psoriasis
4. IBD
5. Type 1 diabetes

Question 2

What is immunological disease?
- Nervous system (neurological autoimmune disease)
- Endocrine system (endocrine autoimmune disease)
- GIT (GI autoimmune disease)
- Bones (rheumatic autoimmune disease)
- Skin (dermatological autoimmune disease)

Answer 2

1. Multiple sclerosis & myasthenia gravis
2. Type 1 diabetes mellitus & Graves’s disease
3. Ulcerative colitis & Crohn’s disease
4. Rheumatoid arthritis & Sjögren’s syndrome
5. Psoriasis & dermatomyositis

Question 3

What is rheumatoid arthritis?

Answer 3

Chronic condition causing pain, swelling, and stiffness in joints, commonly affecting hands, feet & wrists

Question 4

What are DMARDs and give an example?

Answer 4

Disease modifying antirheumatic drugs
Methotrexate

Question 5

How does methotrexate work?

Answer 5

It inhibits dihydrofolate reductase (DHFR), blocking tetrahydrofolate (THF) production needed for purine synthesis, reducing inflammation

Question 6

Why are low doses of methotrexate unaffected by folic acid supplementation?

Answer 6

Folic acid minimises side effects without affecting its efficacy in RA

Question 7

What is the role sulfasalazine in RA treatment?

Answer 7

It is metabolised into active compounds with immunosuppressive, antibacterial, and anti-inflammatory effects

Question 8

How do NSAIDs like indometacin treat RA?

Answer 8

By inhibiting cyclooxygenase (COX) enzymes, reducing prostaglandin production responsible for pain & inflammation

Question 9

Why are COX-2 inhibitors like celecoxib and valdecoxib preferable in RA treatment?

Answer 9

They selectively inhibit COX2, reducing inflammation without GI side effects caused by COX1 inhibition

Question 10

What are the principal types of IBD?

Answer 10

Crohn’s disease and Ulcerative Colitis

Question 11

Compare the use of mesalazine in Crohn’s disease and ulcerative colitis

Answer 11

Mesalazine is more useful for ulcerative colitis than Crohn’s

Question 12

How does mesalazine work?

Answer 12

It decreases prostaglandin & leukotriene synthesis by modulating the inflammatory response in cyclooxygenase & lipoxygenase pathways

Question 13

When are corticosteroids used in IBD?

Answer 13

During acute flare-ups, examples include hydrocortisone, methylprednisolone, & prednisolone

Question 14

What is the advantage of azathioprine over 6-mercaptopurine in IBD treatment?

Answer 14

Azathioprine is a prodrug that is converted to 6-mercaptopurine slowly, providing sustained immunosuppressive activity

Question 15

What is psoriasis?

Answer 15

Long-lasting autoimmune disease causing red, dry, itchy and scaly patches of abnormal skin

Question 16

How does ciclosporin treat psoriasis?

Answer 16

It inhibits T-cell activation by binding cyclophilin, which inhibits phosphatase calcineurin

Question 17

What is acitretin, and how does it work in psoriasis?

Answer 17

A synthetic retinoid that regulates skin cell growth and inhibits keratinisation, used in severe, treatment-resistant cases

Question 18

What are biologics?

Answer 18

Pharmaceutical drugs derived from biological sources, often antibody-based

Question 19

Provide examples of biologics and their uses

Answer 19

1. Belimumab - lupus
2. Adalimumab - RA
3. Vedolizumab - IBD
4. Secukinumab - psoriasis

Question 20

How does adalimumab treat RA?

Answer 20

It binds to TNF, blocking its inflammatory effects by preventing receptor activation

Question 21

What functional groups and bonding are present in methotrexate?

Answer 21

Folate derivative with a pteridine-diamine core, P-aminobenzoyl portion, glutamic acid (with 2 carboxylic acid groups) and asymmetric carbon (results in S and R stereoisomers)
Primary amines - hydrogen bonding
Tertiary amine
Secondary amide
Carboxylic acids

Question 22

What is insulin?

Answer 22

51 amino acid peptide hormone
With chain A with 21 amino acids and B with 30 amino acids

Question 23

Using Cahn-Ingold-Prelog rules assign it either to R or S, what are the functions of R and S?

Answer 23

1st priority NH, 2nd priority COOH and 3rd CH before COOH
Anticlockwise and S form
S - active form, R - impurity

Question 24

What bonding does the carboxylic and secondary amides have in methotrexate?

Answer 24

Ionic bonding so it can be ionised

Question 25

Difference between dihydrofolate and THF

Answer 25

2 reductions on NH within ring, double bonds broken Stops reaction of uracil to thymine (methylation)

Question 26

Why does methotrexate have a stronger affinity for DHFR compared to dihydrofolate?

Answer 26

Electrostatic interaction & additional hydrogen bonding (hydrogen bond donor and ability to ionise) involved with 4-minogroup leads to 1000-fold increase, practically causing irreversible inhibition

Question 27

Mechanism of action with methotrexate in the treatment of RA

Answer 27

Indicates inhibition of purine metabolism is unlikely to be major mechanism of methotrexate in RA and another element must account for efficacy of methotrexate in RA Adenosine signalling pathway is currently leading hypothesis

Question 28

What alternative mechanism of actions are used in methotrexate with RA treatment?

Answer 28

1. Increasing extracellular adenosine levels, have anti-inflammatory effects 2. Modulating immune system activity by inhibiting other enzymes or pathways involved in inflammation

Question 29

What are DMARDs combined with for RA and why?

Answer 29

Sulfasalazine and hydroxychloroquine and other classes of drugs like corticosteroids Increases effectiveness

Question 30

Sulfasalazine metabolism and metabolites

Answer 30

Is a co-drug When metabolised, it forms active metabolites Metabolites have immunosuppressive, antibacterial and anti-inflammatory effects

Question 31

What two aromatic amines are produced when sulfasalazine is metabolised and how does this happen?

Answer 31

Azo (-N=N-) bond breaks (reduced) 5-ASA 5-aminosalicyclic acid: compound retains carboxylic acid and hydroxyl groups on aromatic ring Sulfapyridine: pyridine ring with sulfonamide (-SO2NH2) group, contributes to antibacterial effects, immunomodulatory effects especially but has S/Es in RA

Question 32

What is the first step in the pathway involved in production of inflammatory mediators?

Answer 32

Phospholipids or diacylglycerol (from cell membranes) are converted into arachidonic acid by phospholipase A2 or C action Arachidonic acid serves as precursor for inflammation-related molecules

Question 33

What is the role of COX enzymes in inflammation, and how does this relate to prostaglandins? (step 2)

Answer 33

Arachidonic acid is metabolised by COX-1 and 2 into prostaglandins Prostaglandins are key mediators of inflammation, pain and swelling

Question 34

How do NSAIDs work to reduce inflammation and pain in RA?

Answer 34

NSAIDs inhibit COX-1 and 2 enzymes, reducing prostaglandin productions Alleviates inflammation, pain and swelling associated with RA

Question 35

Indometacin also inhibits synthesis of beneficial prostaglandins in GI tract and kidney (due to inhibiting COX-1), what issues will this cause?

Answer 35

1. GI - prostaglandins PGE2 & PGI2 maintain gastric mucosal barrier by stimulating mucus & bicarbonate (protects stomach lining) causing peptic ulcers, promoting blood flow to gastric mucosa causing serious bleeding or perforation 2. Kidney - PGE2 & PGI2 regulate renal blood flow, in conditions with decreased blood supply (dehydration & hypotension), counteract vasoconstrictive effects of hormones (angiotensin II, NA)

Question 36

Inhibition of COX-1 reduces protective factors of GI tract (stomach lining), increasing risk of?

Answer 36

1. Gastritis: inflammation of stomach lining 2. Peptic ulcers: erosions in stomach or duodenum 3. GI bleeding: due to impaired mucosal repair & increased acidity

Question 37

Inhibiting COX-1 reduces prostaglandin synthesis, which leads to?

Answer 37

1. Reduced renal perfusion: cause acute kidney injury, especially in preexisting renal impairment or volume depletion 2. Sodium & H2O retention: due to altered renal haemodynamics, causing oedema & hypertension 3. Risk of chronic kidney damage: prolonged indomethacin may contribute to interstitial nephritis or papillary necrosis

Question 38

The amino acid at position 523 is part of active site of COX. In COX-1 it is isoleucine, in COX-2 it is valine. Suggest how this information could be used to design drugs that selectively inhibit COX-2

Answer 38

Isoleucine has larger side chain than valine, so less space available in active COX-1 site than COX-2 Drug needs to fit into COX-2 active site but not COX-1 Selectively inhibiting COX-2 ONLY

Question 39

Corticosteroids used to treat IBD

Answer 39

Hydrocortisone & methylprednisolone - severe IBD Prednisone or prednisolone - moderate

Question 40

What does 6-mercaptopurine do?

Answer 40

Suppresses the body's immune response Unfortunately, drug tends to be eliminated from body too quickly Azathioprine slowly converted to 6-mercaptopurine by being attacked by glutathione (GS), allowing more sustained activity

Question 41

In azathioprine E = NO2. If a different group was added, that was less electron withdrawing, how would that affect the rate of conversion into 6-mercaptopurine?

Answer 41

Conversion rate altered depending on electron-withdrawing ability of heterocyclic group Lower electron withdrawing power, slower the breakdown NO2 ensures sufficient conversion, since strong electron withdrawing on heterocyclic ring