Non-steroidal vs steroid drugs

Question 1

What do NSAIDs treat?

Answer 1

• NSAIDs: non-steroidal anti-inflammatory drugs that work by inhibiting cyclooxygenase/COX (important in generating prostaglandins involved in immune system. inflammation, pain and body temp)
• Specific drugs (triptans) are used to treat migraines, they are 5-HT1B/1D receptor agonists that remove vasodilation in which activation of nerve ending by vasodilation removes pain of migraines
• Main effects include:
  1. Analgesia: responds to low-moderate intensity pain, work by preventing prostaglandin synthesis and prostaglandins in relation to analgesia sensitise nerve endings
  2. Anti-inflammatory: inhibiting prostaglandin synthesis reduces inflammation
  3. Anti-pyretic: reduce raised body temp, macrophages phagocytose damaged tissue and release cytokines that reach hypothalamus via blood
• Paracetamol will not reset the body temperature, it will only reduced a raised temperature)

Question 2

Mechanism of action of NSAIDs

Answer 2

• NSAIDs should be taken after eating as prostaglandins act as trophic factors to mucosal cells, causing mucosa to thin so acid in stomach will burn into deeper layers of the stomach (may cause bleeding)
  1. Irreversible inhibition of COX, e.g aspirin
• Aspirin covalently binds to COX active site, covalent bond prevents substrate from entering active site so enzyme will have no catalytic effect
• Effect of aspirin is long lasting as re-synthesis of new enzymes is required to generate new COX capacity
  2. Reversible inhibition of COX, e.g ibuprofen
• Simple competitive inhibitor, ibuprofen competes for active site with substrate (arachidonic acid)
  3. Reversible non-competitive inhibition of COX, e.g paracetamol
• Paracetamol reduces prostaglandin synthesis, it is also ‘kinder to stomach’, post COX activity, acid burns into stomach generating local inflammation creating free radical increasing their concentration to then ‘swap’ paracetamol, regaining COX activity
• There are 2 isomers of COX
  1. COX1 = constitutive enzyme, primarily expressed by mucosa, ubiquitously expressed, inhibition is mostly responsible for gut effects
  2. COX2 = not ubiquitously expressed, primarily expressed by inflammatory cells, expressed is induced by inflammation, ideal target for anti-inflammatory drug as blocking COX2 instead of COX1 has efficacy but GI tract side effects removed

Question 3

Types and functions of steroids

Answer 3

• 3 main type of steroids secreted by the adrenal cortex: glucocorticoids (synthesised at zona fasciculata), mineralocorticoids (synthesised at zona glomerulosa), and androgens (synthesised at zona reticularis)
• Based on cholesterol as they are structurally similar there is cross-over in their pharmacology, they are highly aromatic (important for crossing the lipid bilayer by dissolving)
• 3 main effects: metabolism, negative feedback . and anti-inflammatory/immunosuppressive
  1. Metabolism: not a useful effect, impacts glucose metabolism, protein synthesis, muscle wasting, redistribution of fat, and cause mineral imbalance of Ca2+ (brittle bones)
  2. Negative feedback: controls glucocorticoid circulating levels so controls access in hypothalamus to pituitary to adrenal cortex
• Corticotrophin releasing factors released from hypothalamus causes pituitary to release adrenocorticotropic hormone which reaches adrenal cortex, acts as trophic factor to maintain adrenal cortex integrity and promote release of steroids
• Steroids have negative feedback on hypothalamus and pituitary
  3. Anti-inflammatory/immunosuppressive: steroids impact early symptoms of inflammation, however later stages of inflammation are also reduced meaning reduction in wound healing and proliferation
• Used for suppressing function of immune cells for organ transplantation

Question 4

Mechanism of action of steroids

Answer 4

• Steroid receptors are intracellular receptors and so steroids are highly lipophilic, allowing them to cross cell membrane to access receptors
• Glucocorticoids cross the cell membrane and bind to nuclear receptors, causing them to homodimerize
• Homodimeric receptor translocates to nucleus, receptor glucocorticoid complex binds to glucocorticoid response elements (short sequences of DNA in promoter region)
• Transactivation of gene that codes for lipocortin, inhibits phospholipase A2 that inhibits arachidonic acid which inhibits leukotrienes from impacting various inflammatory responses
• Trans repression would be a negative GRE causing reduction in synthesis of various proinflammatory cytokines by disrupting NFkB-induced activation
• Used in various situations: replacement therapy, anti-inflammatory, immunosuppression, and emesis
• Asthma: glucocorticoids used to suppress inflammation using a salbutamol inhaler (beta2-receptor agonist), acts locally and when activated causes bronchodilation as beta2-receptors coupled to cAMP productions relaxes smooth muscle so bronchioles relax
• Emesis: gut mucosa is rapidly dividing causing lining to thin leading to inflammation and degranulation of enterochromaffin cells which release 5-HT
• Release of 5-HT from gut activates 5-HT3 receptors in brain, specific 5-HT3 antagonists block receptors and prevent activation to reduce nausea, glucocorticoids further reduce effects of nausea by reducing level of 5-HT release