NSAIDs Flashcards
Define autacoid. Give some examples.
Biological factors which act like local hormones, have a brief duration, and act near the site of synthesis
includes:
- bradykinins
- cytokines
- nitric oxide
- histamine
- leukotrienes
- neuropeptides
Define eicosanoid. Give some examples.
Any class of compound derived from polyunsaturated fatty acids (including arachidonic acid) which is involved in cellular activity
includes:
- prostaglandins
- leukotrienes
- thromboxanes
- prostacyclins
Outline the synthesis of prostaglandins in the context of inflammation.
Cell membrane phospholipids converted into arachidonic acid by phospholipase A2
Arachidonic acid converted into prostaglandin-G and then prostaglandin-H by COX-1 and COX-2
Prostaglandin-H converted into prostaglandins D, E, F, and I by specific prostaglandin enzymes
Prostaglandin-E causes:
- vasodilatation
- hyperalgesia
- fever
- immunomodulation
Contrast the pharmacokinetics of COX-1 and COX-2.
COX-1:
- expressed constitutively in a wide range of tissue types (therefore NSAIDs ADRs due to COX-1 inhibition)
- cytoprotective role in gastric mucosa, myocardium, and renal parenchyma by optimising local perfusion
- narrow binding site allows small molecules (e.g. aspirin) to bind
- t1/2 = ~10min (therefore requires constant synthesis)
COX-2:
- expressed constitutively in parts of brain and kidney
- induced by inflammatory mediators (therefore main therapeutic effects of NSAIDs due to COX-2 inhibiton)
- large binding site allows small and large drugs to bind
note: COX-1 and COX-2 work concurrently; prostaglandin synthesis by both enzymes depends on tissue type
Describe the pharmacokinetics of prostaglandins.
Bind to GPCRs
Act by synergising effects of other autocoids e.g. bradykinin, histamine + increased sensitivity of C fibres
- EP1 receptor (Gq) = peripheral nociception (C fibres) via inhibition of K+ channels and increased sodium channel sensitivity —-> increased [Ca2+]i —> neurotransmitter release (activates previously silent C fibres); stimulated by PGE2 released by tissue and neurone surrounding injury
- EP2 receptor (Gs) = vasodilatation via permeating effects of bradykinin and histamine (removal of glycinergic inhibiton increases sensitivity and discharge rate of interneurones)
- EP3 receptor (Gi) = increased heat production and reduced heat loss —> increased core temp. —> kill bacteria
- EP4 receptor
What are the pharmacokinetics of NSAIDs?
Reversible competitive inhibition of COX-1 and COX-2 (compete with arachidonic acid)
Oral (or topical for soft tissue injury)
Therapeutic dose has linear pharmacokinetics
t1/2 10hrs e.g. naproxone
90%-99% bound to plasma proteins via weak ionic bonds
Wide variation in affinity, efficacy, and selectivity
Give some examples of ADRs associated with NSAIDs.
GI disturbances (short-term = 35%, long-term = 10%-30%):
- asymptomatic
- abdominal pain
- nausea
- heartburn
- gastric bleeding
- ulceration
(gastric COX-1 inhibition reduces mucus secretion and mucosal blood flow, and increases acid secretion; offset with PPIs or misoprostol - prostaglandin analogue)
Renal (in HRH compromised due to reduced renal perfusion):
- reduced renal perfusion (PGE2 and PGI2 maintain renal blood flow) —> sodium, potassium, and water retention —> hypertension
- increased bleeding time, increased bruising, increased risk of haemorrhage
Hypersensitivity:
- skin rashes (15%)
- Stevens-Johnson syndrome
- bronchial asthma (10% of asthmatics)
- Reye’s syndrome
note: COX-2 specific inhibitors (e.g. rofecoxib, celecoxib) still have GI ADRs and long-term use increases the risk of CVS ADRs (approved for short-term use only)
What is Stevens-Johnson syndrome?
Immune-complex mediated hypersensitivity disorder causing toxic epidermal necrolysis (epidermis separates from dermis in skin and mucous membranes) and compromised hepatic function
Triggered by medications (inc. NSAIDs, barbituates, etc.), viral infections (e.g. EBV, otitis media), malignancy
What is Reye’s syndrome?
Rapidly progressive encephalopathy in children following recovery from an acute viral illness (e.g. influenza, chickenpox) which was treated with aspirin
Therefore aspirin is contraindicated in children (under 16yrs) unless required to prevent formation of thrombi
Give some examples of drug interactions with NSAIDs.
Low dose opiates = extends therapeutic range for treating pain and reduces ADRs
e.g. co-codamol = codeine + paracetamol
Other NSAIDs (e.g. self-medication) = increased risk of ADRs and compete for plasma protein binding sites (competitive displacement)
Low dose aspirin = compete for COX-1 binding sites, therefore may interfere with cardioprotection from aspirin
Highly protein bound drugs = competitive displacement of drugs from plasma proteins affects pharmacodynamics/kinetics
- increased potency = e.g. sulfonylurea —> hypoglycaemia, warfarin —> increased bleeding, methotrexate —> numerous ADRs
- reduced potency e.g. ACE-inhibitors (blocks production of vasodilating prostaglandins)
Describe the pharmacokinetics of aspirin. What is its mechanism of action? When is it indicated?
IRREVERSIBLY inhibits COX enzymes via acetylation
Hydrolysed to salicylate in plasma
- low dose = first order; t1/2 = ~4hrs
- high dose = zero order
Reduces thromboxane A2 production —> reduced vasoconstriction and platelet aggregation (therefore cardioprotective)
Indicated: CARDIOPROTECTION (75mg) - NOT AS ANALGESIC/ANTI-INFLAMMATORY
+ evidence for GI/breast cancer cancer prophylaxis
Describe the pharmacokinetics of paracetamol. What is its mechanism of action? When is it indicated?
First order kinetics in healthy patients; t1/2 = ~2-4hrs
Zero order kinetics in high (toxic) doses
Unknown mechanism of action - weak COX-1 and COX-2 inhibitor in CNS
8 x 500mg tablets/day
Indications:
- virtually no anti-inflammatory action
- mild-moderate pain
- fever
What is a toxic dose of paracetamol?
Depends on liver function
Single dose > 10g (20+ tablets) is potentially fatal
10 tablets in 1hr can be fatal (esp. in paediatrics and vulnerable adults e.g. reduced hepatic function - alcoholics)
Long-term paracetamol use increases the risk of low-dose toxicity by depleting supplies of glutathione and can cause presbycusis (age-related sensorineural hearing loss)
Reminder: how is paracetamol metabolised?
60% conjugated to glucuronide (Phase 2)
30% conjugated to sulfate (Phase 2)
10% oxidised to NAPQI via cytochrome P450 2E1 (Phase 1)
—> conjugated to glutathione (Phase 2) —> cysteine and mercapturic acid conjugates
Outline the mechanism of paracetamol toxicity. How does it cause liver failure?
Glucuronide and sulfate conjugation pathways saturated
More paracetamol oxidised to NAPQI
Conjugation of NAPQI to glutathione is saturated
Unconjugated NAPQI is highly reactive and nucleophilic —> binds to cellular macromolecules/mitochondria —> loss of function in hepatocytes —> necrotic hepatic cell death —> liver failure
Depletion of glutathione causes damage due to oxygen radicals —> apoptotic hepatocytes
CYP450 enzyme & glutathione conjugation affected in liver disease (more vulnerable to toxicity)
Can also cause renal tubular necrosis and hypoglycaemic coma
