301 Chemistry Flashcards
Examples of immunological diseases
- Rheumatoid arthritis
- Multiple sclerosis
- Psoriasis
- IBD
- Type 1 diabetes
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)
- Multiple sclerosis & myasthenia gravis
- Type 1 diabetes mellitus & Graves’s disease
- Ulcerative colitis & Crohn’s disease
- Rheumatoid arthritis & Sjögren’s syndrome
- Psoriasis & dermatomyositis
What is rheumatoid arthritis?
Chronic condition causing pain, swelling, and stiffness in joints, commonly affecting hands, feet & wrists
What are DMARDs and give an example?
Disease modifying antirheumatic drugs
Methotrexate
How does methotrexate work?
It inhibits dihydrofolate reductase (DHFR), blocking tetrahydrofolate (THF) production needed for purine synthesis, reducing inflammation
Why are low doses of methotrexate unaffected by folic acid supplementation?
Folic acid minimises side effects without affecting its efficacy in RA
What is the role sulfasalazine in RA treatment?
It is metabolised into active compounds with immunosuppressive, antibacterial, and anti-inflammatory effects
How do NSAIDs like indometacin treat RA?
By inhibiting cyclooxygenase (COX) enzymes, reducing prostaglandin production responsible for pain & inflammation
Why are COX-2 inhibitors like celecoxib and valdecoxib preferable in RA treatment?
They selectively inhibit COX2, reducing inflammation without GI side effects caused by COX1 inhibition
What are the principal types of IBD?
Crohn’s disease and Ulcerative Colitis
Compare the use of mesalazine in Crohn’s disease and ulcerative colitis
Mesalazine is more useful for ulcerative colitis than Crohn’s
How does mesalazine work?
It decreases prostaglandin & leukotriene synthesis by modulating the inflammatory response in cyclooxygenase & lipoxygenase pathways
When are corticosteroids used in IBD?
During acute flare-ups, examples include hydrocortisone, methylprednisolone, & prednisolone
What is the advantage of azathioprine over 6-mercaptopurine in IBD treatment?
Azathioprine is a prodrug that is converted to 6-mercaptopurine slowly, providing sustained immunosuppressive activity
What is psoriasis?
Long-lasting autoimmune disease causing red, dry, itchy and scaly patches of abnormal skin
How does ciclosporin treat psoriasis?
It inhibits T-cell activation by binding cyclophilin, which inhibits phosphatase calcineurin
What is acitretin, and how does it work in psoriasis?
A synthetic retinoid that regulates skin cell growth and inhibits keratinisation, used in severe, treatment-resistant cases
What are biologics?
Pharmaceutical drugs derived from biological sources, often antibody-based
Provide examples of biologics and their uses
- Belimumab - lupus
- Adalimumab - RA
- Vedolizumab - IBD
- Secukinumab - psoriasis
How does adalimumab treat RA?
It binds to TNF, blocking its inflammatory effects by preventing receptor activation
What functional groups and bonding are present in methotrexate?
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
What is insulin?
51 amino acid peptide hormone
With chain A with 21 amino acids and B with 30 amino acids
Using Cahn-Ingold-Prelog rules assign it either to R or S, what are the functions of R and S?
1st priority NH, 2nd priority COOH and 3rd CH before COOH
Anticlockwise and S form
S - active form, R - impurity
What bonding does the carboxylic and secondary amides have in methotrexate?
Ionic bonding so it can be ionised
Difference between dihydrofolate and THF
2 reductions
on NH within ring, double bonds broken
Stops reaction of uracil to thymine (methylation)
Why does methotrexate have a stronger affinity for DHFR compared to dihydrofolate?
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
Mechanism of action with methotrexate in the treatment of RA
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
What alternative mechanism of actions are used in methotrexate with RA treatment?
- Increasing extracellular adenosine levels, have anti-inflammatory effects
- Modulating immune system activity by inhibiting other enzymes or pathways involved in inflammation
What are DMARDs combined with for RA and why?
Sulfasalazine and hydroxychloroquine and other classes of drugs like corticosteroids
Increases effectiveness
Sulfasalazine metabolism and metabolites
Is a co-drug
When metabolised, it forms active metabolites
Metabolites have immunosuppressive, antibacterial and anti-inflammatory effects
What two aromatic amines are produced when sulfasalazine is metabolised and how does this happen?
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
What is the first step in the pathway involved in production of inflammatory mediators?
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
What is the role of COX enzymes in inflammation, and how does this relate to prostaglandins? (step 2)
Arachidonic acid is metabolised by COX-1 and 2 into prostaglandins
Prostaglandins are key mediators of inflammation, pain and swelling
How do NSAIDs work to reduce inflammation and pain in RA?
NSAIDs inhibit COX-1 and 2 enzymes, reducing prostaglandin productions
Alleviates inflammation, pain and swelling associated with RA
Indometacin also inhibits synthesis of beneficial prostaglandins in GI tract and kidney (due to inhibiting COX-1), what issues will this cause?
- 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
- Kidney - PGE2 & PGI2 regulate renal blood flow, in conditions with decreased blood supply (dehydration & hypotension), counteract vasoconstrictive effects of hormones (angiotensin II, NA)
Inhibition of COX-1 reduces protective factors of GI tract (stomach lining), increasing risk of?
- Gastritis: inflammation of stomach lining
- Peptic ulcers: erosions in stomach or duodenum
- GI bleeding: due to impaired mucosal repair & increased acidity
Inhibiting COX-1 reduces prostaglandin synthesis, which leads to?
- Reduced renal perfusion: cause acute kidney injury, especially in preexisting renal impairment or volume depletion
- Sodium & H2O retention: due to altered renal haemodynamics, causing oedema & hypertension
- Risk of chronic kidney damage: prolonged indomethacin may contribute to interstitial nephritis or papillary necrosis
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
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
Corticosteroids used to treat IBD
Hydrocortisone & methylprednisolone - severe IBD
Prednisone or prednisolone - moderate
What does 6-mercaptopurine do?
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
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?
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
