Pharmacology (3.3) Flashcards
What is the oral conventional treatment and topical treatment?
Oral conventional tx: Paracetamol, NSAIDs (including aspirin), codeine-containing analgesics.
Topical: NSAIDs, capsaicin (rubefacients)
PGH2 is divided into PGE2, PGD2,PGF2α, PGI2, TXA2
What do these eicosanoids do?
Eicosanoids are derived from arachidonic acid (C-20)
- PGD2 : Mastcells
- PGE2 : Macrophages
- PGF2α : Corpus luteum (contraction of uterus)
- PGI2 : Vascular endothelium
- TXA2 : Platelets
What is the structural differences between COX-1 and COX-2
- COX-1 has a active site
- COX-2 has a hydophilic side pocket and hydrophobic channel
How do NSAIDs work?
- Decrease levels of inflammatory mediators generated at site of tissue injury
- Inhibits cyclooxygenase (this catalyses conversion of aa to pg, sensitize nerves to painful stimuli)
- COX-1(constitutive), COX-2(constitutitve kidney/brain only, induced during inflammation), COX-3 (variant of COX-1 in CNS –> paracetamol wors here)
Describe the inhibition of cox
- Reversible (except Aspirin)
- competitive
- Duration of action depends on pharmacokinetic clearance
- Good oral absorption; protein bound; glomerular filtration or tubular secretion
- Most (including Aspirin) organic acids (actively) –> accumulate at sites of inflammation
- Some NSAIDs – strong O2 radical scavenging effects (secondary action)
Acute relief – use short ½ life (<6h)
Chronic relief – use long ½ life (>12 to 48h)
How does pain relief work?
- Mild analgesics
- Type of pain & level of intensity affect usefulness
> effective against pain due to local stimulation of pain fibres & hyperalgesia
> Eg, Endometrium release of PG during menstruation
> Bradykinin, TNFα, IL-1 all cause activation of prostaglandin-sensitive nociceptors
- May also affect CNS, but at sites removed from opioid drugs
Headache relief: removal of vasodilator effect of cerebral vasculature
How does relief of fever work?
- infection or tissue damage
- Enhanced production of IL-1, IL-6, INF-α & β, TNFα
- increased synthesis of PGE2 in hypothalamus –> this region controls temp regulation
- PGE2 causes increase in body temp
NSAIDs reduces the PGE 2 - countering the effect above
How do selective inhibitors work specifically COX-1 and COX-2
Inhibit cox-2 but not cox-1
- *Cox-1:** constitutive - homeostasis
- *Cox-2:** induced during inflammation
- large amounts of prostaglandins at site of inflammation
- main cause of pathophysiological process
- different sub set of PGs created
Inhibition supposed to share physiological PG synthesis (much less side effects)
What are side effects of current NSAIDs
Gastrointestinal ulceration - bleeding (MOST COMMON)
- Ibuprofen/diclofenac (low)
- COX-2 inhibitors (lower)
- Use misoprostol (PGE1 analogue) to act on pariteal cells
Skin reactions - topical NSAIDs
- Mild rashes
Blockade of platelet aggregation
Inhibition of uterine motility
Renal function
- Decreased blood flow
- Congestive heart failure if renal disease present
- Increased NA and h20 retention
- Increased K+ reabsorption
May cause hypertension
Hypersensitvity reactions
- Aspirin most pronounced – bronchospasms
- Mechanism via excess leukotrines
Dementia in elderly
CI of NSAIDs?
- Active peptic ulcer. GI bleed
- Aspirin hypersensitivity
- Considerations
Considerations
- Direct heart issues, hypertension, asthma, renal impairment, surgery, elederly, 3rd trisemester pregnancy - breastfeeding
Paradoxical effects of NSAID
NSAIDs potential to be pro-inflammatory
- PGE2 and PGI2
- Reduce toxic O2• from neutrophils
- Reduce lymphocyte action
- Reduce lysosomal enzyme release
NSAIDs would reverse this
> long term, could worsen condition
For paracetamol (Acetaminophen);
A) How does it work
B) Advantages
C) Side effects
D) Metabolism
A)
- Analgesic & antipyretic effects similar to aspirin
- COX inhibition in CNS (COX-3)
- weak anti-inflammatory effects in periphery
- no effect on cardiovascular or respiratory systems
- No acid-base changes
B)
- no gastric effects: ie bleeding, irritation or erosion
- no platelet effects
- substitute for aspirin for headache,fever and use with NSAIDs in RA and OA
C)
- occasional rash
- chronic use - renal toxicity
D)
- 2-4 hour plasma ½ life
- 4-8 hours for very high doses
- If overdose (saturation of normal conjugating enzymes) –> increase glutathione in cells to overcome toxicity
For Aspirin (acetylsalicylic acid);
A) How does it work
B) What is it used for
C) toxicities?
D) Kinetics
A)
- Non selective
- Irreversible acetylation of different serine residues between COX-1 & COX-2
- Prevents access of arachidonic acid to active site of COX
- Duration of effect determined by tissue capacity to regenerate COX
- Stimulates lipoxin synth (Act on PMN-leukocytes to oppose proinflam action = “stop signal”)
B)
- Benchmark for inflammation treatment in RA
- Alleviate pain, fever in inflammatory conditions
- Antipyretic
- Reduces risk of colon cancer,cvd (for diabetics in elderly)
C)
- Chronic - headache, nausea, tinnitus, confusion, drowsiness
- Severe - convulsions, coma, acid-base disturbances, haemorrhagic phenomena, hyperpyrexia, cardiovascular collapse, CNS depression
D)
- Dose dependent
- Only aspirin covalent binding of COX
- rapid hydrolysis to salicylate
- t ½ for platelet action (15 min) – most common use
- t ½ for general action 3h - 15h (dose dependant)
What is Reyes syndrome?
- Do not use salicylates (Aspirin) in children or adolescents with chickenpox or influenza
- Severe hepatic injury
- Encephalopathy
- Aspirin and viral illness may combine to damage mitochondria
- Increased CO2 = increased respiration
- Increased water sweat + respiratory acidosis
- Rare but often fatal
Interactions of aspirin
- increases effect of warfarin (aspirin only)
- reduce urate excretion
- interferes with probenecid and sulfinpyrazone
- Methotrexate - impairs excretion
- Reduces effectiveness of ACE inhibitors
What are fenamates used for?
Mefenamic Acid (Ponstan/Mefic)
- dysmenorrhoea (period cramps)
- inflammation associated pain
Short half life (2-4 hours)
Most common side effects:
- 25% G.I. tract – including diarrhoea
- some isolated haemolytic anaemia
- Some skin rashes
What are heteroaryl acetic acids? Give some examples
Diclofenac (Voltaren)
- RA, OA, AS
Ketorolac (Toradol)
- post operative pain
What are some examples of Arylpropionic acids? What are they used for
Ibuprofen, Naproxen, Ketoprofen, Tiaprofenic Acid
- RA, OA, AS, Acute gouty arthritis, tendonitis, bursitis, dysmenorrhoea, migraine
- Comparable to aspirin
- Less side effect intensity than high dose aspirin
- Drugs of choice
- Ibuprofen for patients with NSAID GI problems
- 99% plasma protein bound
- All alter platelet function & prolong bleeding time
- Ibuprofen – liver metabolised % renal cleared
What are enolic acids? What are they used for
Piroxicam (Feldene), Meloxicam (Mobic)
- RA, OA, AS
- Equivalent to aspirin
- Long half life (30-60h)
- Single daily dose
- Effects on neutrophil activation, COX & collagenase
- Greater Na+ & H2O retention
What is diaryl substituted pyrazole?
Celecoxib
- Contra-indications: if hypersensitive to other NSAID or with allergies to sulfonamides
- OA, RA, dysmenorrhoea
- More selective for COX-2
What is Parecoxib (dynastat)
Prodrug of Valdecoxib (itself removed from sale)
- IM (slow and deep) or IV inject (bolus ok)
- Only for post operative pain relief
- Onset of analgesia (10min) , peak effect <2 hours
- increased risk of cardiovascular - thrombotic complications & anaemia. Also risk of renal impairment
General points
- If no beneficial effects seen in 2-3 weeks –> try another NSAID
- No need to combine NSAIDs – no added effects
- If on high level NSAIDs for extended periods (check liver function, blood count, creatinine CLR yearly)
- New evidence of hearing loss across whole group
- Codeine = part of nsaid combinations
What is codeine?
- Analgesic effect depends exclusively on demethylation to morphine
- Converted to morphine by CYP2D6
- Effect and side effects similar to low-dose morphine
- Incidence of nausea and constipation limits its use
- Given orally for mild to moderate pain
What is Capsaicin - desensitiser
- One of active ingredients of pepper spray (from Chilli peppers)
- Seemingly paradoxical use of a pain causing agent to initiate pain relief
- Allows so much extra Ca2+, Na+ & other cations into cell that it leads to nerve terminal degeneration
- Takes many days to weeks to recover and heal the damage caused
- In meantime – nerve terminal not able to forward signal to brain
- initial sharp pain, followed by no pain for days. Also causes Vascular relaxation, increasing blood flow to skin (Rubefacient)
Adverse effects
- If pain or original irritation in skin is strong prior to application – then further irritation caused by this agent may limit use in overly sensitive patients
- Hypothermia: This should not occur if only used in localised topical settings
