Flashcards in CPTP 3.14 Drugs used in Inflammation Allergy and Pain 2 Deck (55)
How do the pain-alleviating mechanisms of NSAIDs differ when used for headaches?
Instead of reducing sensitisation from prostaglandins, the main pain-alleviating effects actually come from decreased PG-mediated vasodilation
What are the common side effects of NSAIDs? What type of ADR is each?
GI disturbances: TYPE A
• COX-1 inhibition removes the protective mechanism of prostaglandins (causes vasodilation, decreased acid secretion and increase mucous secretion)
Skin reactions: TYPE B
• Toxic epidermal necrosis
Renal effects: TYPE A
• Prostaglandins are involved in maintenance of normal kidney functions
As a rule of thumb, what type of ADR are allergies and hypersensitivities?
Outline the NSAIDs in order of selectivity for COX-1
Most selective for COX-1
Least selective for COX-1, most selective for COX-2
(typically COX-2 is the better pharmacological target, as these are the ones induced in inflammation)
Describe the pharmacodynamics of aspirin
• Irreversible antagonist of COX-1 (weakly COX-2)
• Also inhibits NFKB (k=kappa) an inflammatory cytokine
• Anti-platelet activity
Describe the pharmacokinetics of aspirin
• It's a weak acid, and so is mostly neutral in the acidic stomach, facilitating its passage across the mucosa
• Regardless, most is still absorbed in the ileum due to its extensive surface area
• Aspirin is rapidly HYDROLYSED, yielding salicylate
METABOLISM AND EXCRETION:
• 25% oxidised
• Some is conjugated
• 25% excreted unchanged
Which subclass of NSAIDs are inhibitors of COX 1 and 2 (but mostly 1)?
What type of inhibitor are these?
Which of these inhibits leukocytes?
Propionic acid derivatives:
These are competitive inhibitors
Describe the pharmacokinetics of propionic acid derivatives with respect to:
• Route of admission
• State in plasma
• Well absorbed orally
• Extensively plasma protein bound (>99%)
• Metabolised in liver, excreted by kidneys
Why should conditions which alter plasma protein concentration be considered when using drugs such as propionic acid
It increases the amount of free drug in the blood, due to the lack of availability of plasma proteins (e.g. albumin)
As a result, there is an increased chance of a toxic side effect (as free drug is the pharmacologically active proportion)
Which NSAID is best for arthritic joint pain alleviation and why?
Propionic acid derivatives, because they can penetrate arthritic joints
Which formulary drug is COX-2 selective and does not bind to COX-1?
What are the adverse drug effects for celecoxib?
State the half life of:
1) 2 hours (short acting)
2) 11 hours (long acting)
3) 11 hours
Describe the pharmacokinetics of celecoxib
• Absorbed orally
• 90% plasma protein bound
• Lipophilic --> accumulates in fat
• Metabolised by CYP450s
• Excreted in faeces and urine
What other mechanism of action does celecoxib have?
Central analgesic effect, as it is lipophilic and can cross the BBB
What are the benefits of celecoxib?
They have no GI side-effects (although be careful due to CVD effects)
What main tissues is serotonin produced in?
• Intestine wall
• Blood platelets
What is serotonin broken down by, and what into?
Broken down into 5-HIAA
What are the effects of serotonin on blood vessels?
They have different effects depending on the receptor:
What causes MIGRAINES?
• Vasodilation occurs due to serotonin release stimulating 5-HT2 and subsequent NO release
• NO stimulates sensory nerves, causing nociception and also central pain sensitisation
• Then there is positive feedback, as the sensory nerves release neuropeptides, which cause neuroinflammation then further NO release, sensitisation and stimulation
Describe how serotonin causes vasodilation when acting on 5-HT2 receptors. What does this cause when occurring in the brain?
• Acts on endothelial cells causing NO release
• Acts on neurones to inhibit noradrenaline release from nerve terminals
This causes headache
How can migraines be prevented?
How can migraines be acutely treated?
• These cause constriction
• They also directly inhibit the sensory nerves and prevents the neuropeptide release
Name the formulary migraine drug, which mechanism it uses, and its route.
• 5-HT1 agonist
• SC, intranasal
• Can be given orally but poor absorption