Lecture 6 - Therapeutics for inflammation Flashcards
H1 receptor antagonists: what is the difference between H1 and H2, what do they do, how many generations are there, what side effects, and what happens when it is injected intradermally?
H1 - inflammation
H2 - homeostatic
- Inflammation
- release of proinflammatory mediators
- activation of eosinophils
- expression of adhesion molecules
first, second and third-generation
Sedation, peripheral antimuscarinic
We observe the triple response (red, wheal flare), including vasodilation of the small arterioles and precapillary sphincters and an increase in vascular permeability. We know that histamine has a role in other areas too – release of proinflammatory mediators, eosinophil activation and expression of adhesion molecules
NSAIDs - prostaglandins: what are they and what do they do?
Non-steroidal anti-inflammatory drugs - Don’t have a direct effect on the inflammatory process - they suppress the signs and symptoms by inhibiting the binding of arachidonate to COX enzymes
- Anti-inflammatory: decrease in PGE2 and PGI2. Indirect inhibition of oedema
- Analgesic: decreased PG synthesis results in less sensitisation of nociceptors to bradykinin and 5-HT
- Anti-pyretic: IL-1 releases PGEs in the CNS > elevate hypothalamic set point.
COX: what forms are there, what do they do, and what do the drugs against them do?
COX-1 - constitutively (always) produced and expressed in most cells including platelets, role in homeostasis, GI protection, renal blood flow, and platelet aggregation
COX-2 induced in inflammatory cells
Drugs against COX-1 result in increased acid secretion and decreased blood flow to the stomach & kidneys
Drugs against COX-2 result in decreased vasodilation and oedema
Classification of NSAIDs
COX-1 inhibitors are specific for COX-1 (low-dose aspirin)
COX-2 inhibitors are specific for COX-2 (meloxicam)
Highly selective COX-2 inhibitors are specific for COX-2 (celecoxib, etoricoxib)
Non-selective COX inhibitors, (ibuprofen, indometacin, and high-dose aspirin)
How do COX-enzymes bind with arachidonate?
Both COX-1 and COX-2 have a hydrophobic channel which allows arachidonate binding, causing the typical cascade of reactions
How do COX inhibitors inhibit COX enzymes?
COX inhibitors bind to COX-1, inhibiting its binding with arachidonate
COX-2 inhibitors can also bind to its ‘side pocket’, inducing a conformational change, preventing arachidonate binding
Gastrointestinal adverse effects of NSAID use and their mechanism
- Gastric ulceration - due to inhibited gastric mucosa blood flow
- Discomfort
- Nausea
- Diarrhoea
- Ulceration
- Bleeding
Chemical irritancy, gastric acid reflux, loss of homeostatic PGs, ischaemia, and gastric mucosa breakdown
Renal adverse effects of NSAID use and their mechanism
- Fluid retention
- Electrolyte disturbance
- Renal failure
Loss of homeostatic PGs
Cardiovascular adverse effects of NSAID use and their mechanism
- Exacerbation of hypertension
- Exacerbation of congestive heart failure
Secondary to renal disturbances
Pulmonary adverse effects of NSAID use and their mechanism
- Exacerbation of asthma
Loss of homeostatic PGs, increase in leukotriene production
Haematological adverse effects of NSAID use and their mechanism
- Hemorrhage
Decreased TXA₂ production
What does aspirin do?
Irreversibly inhibits COX enzymes for the lifetime of platelet (~10 days)
Glucocorticoids: what are they and what do they do?
Inhibit phospholipase A2 and induction of cyclo-oxygenase
5-lipoxygenase inhibitors: what are they and what do they do?
TXA2 synthase inhibitors: what are they and what do they do?
PG antagonists: what are they and what do they do?
Leukotriene receptor antagonists: what are they and what do they do?
Inhibits LTD4
Montelukast - used to treat asthma
PAF agonists: what are they and what do they do?
Platelet-activating factor antagonists
Adrenal cortex: what are the three layers and what do each produce?
zona glomerulosa (outermost) - produces mineralocorticoids, main hormone is aldosterone which regulates water and electrolyte balance
zona fasciculata (middle) - glucocorticoids, main hormone is hydrocortisone/cortisol (corticosterone in rodents)
zona reticularis produces androgens
Glucocorticoid production
- Hypothalamus reacts to stress
- Corticotropin-releasing hormone (CRH) is released
- CRH acts on the anterior pituitary and produces adrenocorticotropic hormone (ACTH)
- ACTH acts on the adrenal cortex (zona fasciculata) to produce cortisol
- Cortisol does negative feedback on the hypothalamus and anterior pituitary gland as well as activating various physiological effects
What does cortisol do?
- Gluconeogenesis
- Fat metabolism
- Protein metabolism
- Anti-inflammatory actions
Exogenous glucocorticoids: what do they do and what are the examples?
Modify expression of many genes > approx. 1% of the total genome is affected, resulting in:
* Suppress immune system (innate & adaptive)
Increased blood glucose levels, stimulate CHO, fat and protein metabolism, and decreased bone formation
- hydrocortisone (topical)
- prednisolone
- prednisone (pro-drug)
- methylprednisolone
- betamethasone
- dexamethasone
Why is cortisol highly prevalent when you wake up?
Blood-glucose level relations: your body has fasted so energy is moved around the body
Fludrocortisone: how potent is it?
Some of the glucocorticoids have such high mineralocorticoid activity that their anti-inflammatory glucocorticoid effects are of no benefit
For example, the mineralocorticoid activity of fludrocortisone is so high that its anti-inflammatory activity is of no clinical benefit
Lipophilic
Can passively diffuse into the membrane
How do steroids cause an effect on the genome?
Steroids diffuse into the membrane, dimerise with a receptor (SR dimer) then enter the nucleus and bind to a hormone response element (HRE) region and affect the genome, either upregulating or downregulation protein production
Steroids: their anti-inflammatory effect on cells
Decreased transcription of genes for adhesion proteins and cytokines:
* Reduced migration of leukocytes (neutrophils) from blood vessels into the epithelial cells
* reduced activation of neutrophils, macrophages & mast cells & T-helper cells
* reduced T cell proliferation
* reduced fibroblast action: decrease collagen & glycosaminoglycans production and decrease healing and repair
How do steroids affect mediators in inflammation?
Reduces the production of the following mediators:
* Eicosanoids (via inhibition of PLA2 & COX-2)
* Cytokines: IL-1-6, IL-8, TNFα, cell adhesion factors & GM-CSF (granulocyte-macrophage colony-stimulating factor - important in leukocyte growth factor)
* Plasma complement proteins
* NO by induced NO synthase (iNOS)
* Histamine release
* IgG
pro-anti-inflammatory actions:
* Increased synthesis of IL-10 and annexin-1 - two mediators that have anti-inflammatory actions
Exogenous corticoids: adverse effects
- Euphoria
- Osteoporosis
- Tendency to hyperglycaemia
- Negative nitrogen balance
- Increased appetite
- Increased susceptibility to infection
- Obesity
Inhaled steroids:
* oral candidiasis
* Local immunosuppression
oral steroids:
* Bruising
* Weight changes
* Osteoporosis
* Adrenal suppression
Long-term issues of taking exogenous glucocorticoids
Adrenal suppression
steroid treatment supplements replace endogenous cortisol and steroid treatment leads to decreased CRH and ACTH release
patients on course of steroid therapy >3 weeks must not suddenly stop treatment: Addisonian crisis
DMARDs: what are they, when are they used, what do they do, and what examples of them are there?
Disease-modifying antirheumatic drugs
One of the first drugs somebody takes as they modify the disease itself
immunosuppressants:
* methotrexate
* azathioprine
* cyclosporin
Antimalarials:
* chloroquine
gold salts:
* sodium aurothiomalate
* auranofin
Miscellaneous:
* penicillamine
* sulphasalazine
* levamisole
* tacrolimus
Methotrexate: what is it and what is its process?
An immunosuppressant DMARD
- Folate analogue
- Reversible inhibitor of dihydrofolate reductase - used in cancer treatments (affects cell proliferation): reversible inhibitor of dihydrofolate reductase - a crucial enzyme in synthesising purine and pyrimidine in many organisms, including bacterial and protozoa, causing Mammalian cells to be arrested in the S phase of the cell cycle
- anti-inflammatory effects: Methotrexate inhibits AICAR transformylase, resulting in an increase in intracellular AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) levels which in turn inhibits the enzymes responsible for the catabolism of adenosine and AMP - as a result, the levels of extracellular adenosine increases
SUMMARY: Methotrexate inhibits AICAR transformylase which, through enzymes, causes an increase in AMP, causing more adenosine to be formed - adenosine increases IL-10 (anti-inflammatory.), inhibits the production of ROS, LTB4, TNFα, IL-6 & 8, reduced expression of E-selectin
azathioprine: what is it, what does it do, and what are the possible side effects?
An immunosuppressant DMARD
- Used to treat inflammatory bowel disease, autoimmune diseases, e.g. RA; tissue rejection
- Metabolised to mercaptopurine, a purine antagonist that inhibits DNA synthesis.
Side effects include liver toxicity and bone marrow suppression
cyclosporin: what is it, what does it do, and what are the possible side effects??
An immunosuppressant DMARD
- Used to treat ulcerative colitis, tissue rejection, RA
- T-cell selective immunosuppressant
- Inhibits IL-2 gene transcription
The most significant side-effect is kidney toxicity
chloroquine: what is it, what does it do, and what are the side effects?
Anti-malarial DMARD (aka hydrochloroquine)
- Down-regulate T-cell activity
- Used to treat RA plus systemic lupus
- Anti-inflammatory action is slow. Usually used with NSAIDs
Side-effects: irreversible retinopathy, ototoxicity, myopathy with long-term use
sodium aurothiomalate: what is it and what does it do?
Gold salt DMARD
Intra-muscular injection with a slow onset of action (months)
auranofin: what is it and what does it do?
Gold salt DMARD
Inhibits induction of IL-1 and TNF-α with slow onset of action (months)
penicillamine: what is it and what does it do?
Miscellaneous DMARD
Reduces numbers of T-lymphocytes, inhibits macrophage function, decreases IL-1 and rheumatoid factor, and prevents collagen from cross-linking.
sulphasalazine: what is it and what does it do?
Miscellaneous DMARD
Scavenges toxic free radicals produced by neutrophils.
levamisole: what is it and what does it do?
(google ig?)
tacrolimus: what is it and what does it do?
Miscellaneous DMARD
An antibiotic which inhibits T-lymphocyte signal transduction and IL-2 transcription.
Adenosine: what does it do in regards to inflammation?
Increase IL-10 (anti-inflammatory interleukin)
inhibits production of ROS, LTB4, TNFα, IL-6 & 8
reduced expression of E-selectin
Anticytokine drugs: what are they, what are the targets, when are they administered, how are they administered, what results do they achieve, and what side effects are present?
Anti-inflammatory drugs
- TNF-α
- IL-1, -6, -12 and -23
- T and B cells
Later on - they are quite expensive
Plant-based - lack of oral bioavailability - injection required
DAS28 (disease activity score from assessment of 28 joints) score is reduced significantly after the first 3 months of treatment - lower the score, the less painful the joints
long-term risk of infection & malignancy with TNF-α antagonists? TB, hep. B reactivation, septicaemia, lymphoma
Anticytokine drugs: examples of them
- Adalimumab
- Infliximab
- Etanercept
- Golimumab
- Anakinra
- Tocilizumab
Adalimumab: what do they target and when is it used?
TNF (neutralises)
Inflammatory arthritis; Crohn’s
Infliximab: what do they target and when is it used?
TNF (neutralises)
Inflammatory arthritis; Crohn’s; colitis
Etanercept: what do they target and when is it used?
TNF (decoy receptor)
Inflammatory arthritis
Golimumab: what do they target and when is it used?
TNF (neutralises)
Inflammatory arthritis; colitis
Anakinra: what do they target and when is it used?
IL-1 (R antagonist)
Inflammatory arthritis
Tocilizumab: what do they target and when is it used?
IL-6 (R antagonist)
Inflammatory arthritis
Drugs ending in mab: what is the meaning?
Monoclonal antibody
