IC13 analgesics Flashcards
what is the phospholipase a2 breakdown
phospholipase A2
= arachidonic acid
= cox, and lipoxygenase
cox
= 1) PGE2 (prostaglandins) = for pain and vascular permeability
= 2) PGI2 (prostacyclin) = for vasodilation and inhibiting platelet aggregation
= 3) TXA2 = for vasoconstriction and platelet aggregation
what does corticosteroids and nsaids inhibit in the phospholipase a2 breakdown
steroids = inhibit phospholipase a2 directly
NSAIDs = cox
mechanism of action of nsaids
block production of prostaglandins
role of prostaglandins is to increase the sensitisation of nociceptive fibres to stimulation by other inflammatory mediators.
*note that leukotrienes and bradykinin are also sensitisers…
also has additional analgesic actions in the CNS.
mechanism of antipyretic action of aspirin
cox inhibition (and prostaglandin) in the hypothalamus of the brain = reducing body temperature
- note that it does not alter normal body temperature.
what is the mechanism of aspirin ADRs?
low dose is due to cox inhibition,
high dose is due to salicylate toxicity.
what are the aspirin side effects related to salicylate toxicity?
tinnitus
uricosuric
central hyperventilation
respiratory alkalosis
metabolic acidosis
respiratory alkalosis
fever, dehydration
hypothrombinaemia
vasomotor collapse
coma
respiratory and renal failure
what is rare condition associated w aspirin and what increases risk
risk increases if aspirin taken by children with viral infections
causing reyes syndrome = swelling of brain (encephalitis) AND liver
sx ( vomiting, personality change, listlessness [no interest], delirium, convulsions, LOC)
additional mechanisms and side effects of indomethacin?
strongly anti-inflammatory due to additional steroid-like phospholipase A inhibition
HOWEVER CNS effects: confusion, depression, psychosis, hallucinations.
additional mechanisms of diclofenac (relate to side effects)?
short half-life in plasma (less GI risk)
longer half life in synovial fluid = useful in inf joint disease
effects of prostaglandins on GI?
more specifically cox1
reduce gastric acid secretion
increase mucosal blood flow
increase secretion of mucus
increase secretion of bicarbonate
GI related side effects of NSAIDs
dyspepsia, NV
ulcer formation
potential haemorrhage
increase risk of peptic ulcer if >5 days of use
renal adverse effects of NSAIDs?
inhibition of PGE2 and PGI2
PGE2 inhibition:
- sodium (pge2 inhibits na+ reabsorption in TAL thick ascending limb) and water retention, peripheral edema, hypertension
PGI2 inhibition
- suppression of RAA
- hyperkalemia (pgi2 stimulates secretion of RAA; RAA involved in k+ excretion & na+ reabsorption; distal convoluted tubule DCT)
- acute renal failure
risk factors for NSAIDs-induced AKI
1) increasing age >65yo), chronic HTN, atherosclerosis = narrowing of renal arterioles (reduced capacity for renal afferent dilation)
2) pre-existing glomerular disease or renal insufficiency = renal afferent dilation (to maintain GFR)
3) volume depletion
- true: gi/renal salt and water loss, blood loss, diuretic use
- effective: cirrhosis, heart failure
= stimulates AngII secretion
4) ACEi/ARB
= prevent efferent vasoconstriction to maintain GFR
5) triple whammy: acei/arb + diuretic + nsaid
resp/derm side effects of NSAIDs and caution
psuedo-allergic side effects
- skin rash, swell, itching, nasal congestion, anaphylactic shock
asthma
caution in patients with asthma, chronic urticaria, nasal polyps
mechanism of resp/derm SE of NSAIDs
cox inhibition = increased AA = increase leukotrienes = bronchospasm in asthmatics (LTD4) and allergic reaction like symptoms.
heme side effect of NSAIDs (incl mechanism) and caution?
bleeding risk (higher risk in cox 1 > cox 2)
caution in patients who are going for surgical procedures or are initiated on antiplatelet therapy
advantage of cox2 over cox 1
cox 2 plays a more significant role in inflammation and analgesia(?)
cox 1 involved in housekeeping.
where is cox2 expressed in?
CNS
renal
female reproductive tract
synovium
what are some unwanted SE of cox2 inhibition? (and related contraindications)
1) renal toxicity
2) effects on ovulation - delayed follicular rupture.
3) premature closing of ductus arteriosus (fetal lung bypass) in late pregnancy
CONTRAINDICATED IN THIRD TRIMESTER OF PREGNANCY (last pregnancy)
impact of cox2 inhibition on wound healing?
cox2 inhibitors impair wound healing and may exacerbate ulcers.
impact of cox2 inhibition on heme?
selective inhibition causes a relative increase in TXA2 = increase in platelet aggregation = increased risk of thrombosis
heme caution in nsaids? include mechanism
renal effect = hypertension
prothrombotic effect
= risk of heart attack and stroke.
caution
in elderly and
hx of Cardio/CerebroVD (CVD)
overall contraindications for nsaids:
1) eGFR <30 (severe kidney impairment)
2) severe heart failure
3) active GIT ulcer or bleeding
4) bleeding disorders eg haemophilia
5) use of systemic corticosteroids /antiplatelets/ anticoagulants
6) multiple risk factors for toxicity eg elderly + history of bleeding
7) third trimester of pregnancy
which are the cox 2 selective nsaids?
mefenamic acid
celecoxib
diclofenac
etoricoxib
possible MOA for paracetamol
CNS selective cox inhibition
useful as an antipyretic
disadvantages of paracetamol
weak anti-inflammatory
toxic doses can cause
- N/V and
- liver damage
mechanism of paracetamol toxicity
chronic alcohol use or abuse
and overdose
causes an increase in toxic metabolites (minor pathway) = hepatotoxicity
glutathione METABOLISES toxic metabolite to non toxic, but is depleted by alcohol and paracetamol overdose
how to reverse paracetamol toxicity
NAC helps to replenish glutathione.
counselling for paracetamol,
caution (and dose reduction) in underweight, significant liver disease, cachectic (weakness/wasting), frial.
AVOID ALCOHOL
overdose of paracetamol and relevant procedures?
if ≥10g/day = ED
if ≥4g per 24h = increase risk of harm
paracetamol and nsaid combination?
alternating ibuprofen and paracetamol can have sustained antipyretic effect
but combining can have synergistic analgesic effect.
additonal moa of tramadol
weak opiod + SNRI
opioid analgesic side effects
GI: N/V consitpation
hormonal & respiratory effects
depression
falls and fractures
sedation or drowsiness
tolerance, physical dependence, addiction, withdrawal
opioid-induced hyperalgesia
opioid risk factors
1) combination w cns depressants
2) mental health condition
3) renal/hepatic insuff
4) >65 yo
5) pregnant
6) history of substance abuse disorder
MOA of orphenadrine
tertiary amine that cross BBB
muscarinic receptor antagonist
central muscle relaxant
additionally: h1, NMDA, NE, DA reuptake inhibitor, CCB
adr of orphenadrine
common: N/V,
Anticholinergic: flushing, dilated pupils. dry mouth
high dose:
CV: tachycardia,
Motor: ataxia, nystagmus,
CNS: drowsiness, delirium, agitation, visual hallucinations
drug drug interactions with orphenadrine
combination w cns sedatives/depressants = caution
may have additive DDI with 1st gen antihistamines, anticholinergics, and antiparkinsonian drugs.
